MA Study Guide Test 2

Lecture 07 – Muscle – Kane

Types of muscle
- Striated muscle
o Skeletal – voluntary muscle
o Cardiac – involuntary – in heart and its junction with pulm veins
- Smooth muscle
o No striations – involuntary –
o located in vessel walls, organs, dermis of skin, and glands
Muscle Terms
- sarcolemma – plasma membrane
- sarcvoplasm – cytoplasm
- sarcoplasmic reticulum – smooth endoplasmic reticulum
- sarcosomes – mitochondria
- Mus le cell = muscle fiber = myofiber
Skeletal Muscle
- Long cylindrical cells
- Multinucleated with peripheral nuclei
- Striations in longitudinal section
- Connective tissue and capillaries between cells/fibers
- Muscle spindles –sensory structures (proprioceptors) in skeletal muscle – stretch receptor
o 2 connective tissue capsules (inner and outer capsule)
o 2 spaces created by the capsules – periaxial space (b/t outer and inner capsule) – axial space (within the
inner capsule)
o Intrafusal muscle fibers – pink fibers within the inner capsule
o Extrafusal muscle fibers – muscle fibers outside the spindle – larger in diameter than intrafusal muscle
fibers

Skeletal Muscle Investments (transfer contractile motion)

- Endomysium - Surrounds individual cells/fibers - Reticular fibers - Basal lamina
- Perimysium – surrounds fascicles - collagenous
- Epimysium – surround entire muscle - collagenous
Red and White Skel. Muscle Fibers
- Red
o Rich vascularization and and myoglobin
o Slow – twitch fibers – slow contraction – weak repetitive, not fatiguesd (e.g. anti-gravity)
o Numerous mitochondria
o Smaller fiber diameter
o Not extensive sarcoplasmic reticulum
- White
o Poor vascularization and myoglobin
o Fast-twitch fibers, strong, easily fatigued
o Few mitochondria
o Larger fiber diameter
 o Extensive sarcoplasmic reticulum
Skeletal Muscle Cell
- Multinucleated cell
o Arise from fusion of many embryonic myoblasts
o After puberty grows by hypertrophy (vs. hyperplasia)
o As cross-sectional area increases –> number of myofibrils increases –> contractile force increases
- Myofibrils
o Run parallel to long axis of fiber
o Striated
o Striations are in register
 A band (dark, anisotropic): contains H band and M line
 I band (light, isotropic); contains Z/disk/ line
- Sarcomere
o Z line to Z line in myofibril
o The functional contractile unit within the cell

Myofibers (muscle cells)  contain Myofibrils  contain Myofilaments

- Thick Filaments (composed of myosin II)

- Thin filaments
o Composed of actin
 G-actin polymerizes to form F-actin with plus and minus ends
o Tropomyosin (1 tropomyosin per 7 G-actin molecules
o Troponin
 TnT binds tropomyosin to actin
 TnC binds Ca++
 TnI inhibits actin-myosin binding in absence of Ca==
- Heads of myosin molecules in thick filaments attach to actin binding sites in thin filaments
- Tropomyosin blocks myosin binding sites on actin unless Ca++ is bound to troponin (TnC)
Other Skeletal Muscle Proteins
- A-actinin – anchors plus ends of thin filaments to Z disk
- Desmin – intermediate filament; keeps myofibrils in register at Z disk
- Dystrophin – links a- actinin/desmin complex to sarcolemma
- Myomesin – crosslinks adjacent thick filaments at M line
- Titin – forms elastic lattice; anchors thick filament to Z disk
- Nebulin – Z disk protein; assists a – actinin to anchor thin filaments to Z disk
- Tropomodulin – caps minus ends of thin filaments
- C protein – binds to thick filaments at M line
- Cap Z – Z disk protein; caps the plus end of thin filaments

Sarcoplasmic Membrane System

- Transverse (T) tubules
o Invaginations of sarcolemma (PM) into the cell to surround myofibrils
o Located at junction of A and I bands
o Permit depolarization of sarcolemma to be transmitted throughout the cell
- Terminal cisternae
o Dilated portions of the sarcoplasmic reticulum
o Flank t tubules
o Have voltage-gated Ca++ release channels
- This membrane system permits rapid, synchronous release of Ca++ from sarcoplasmic reticulum into the
sarcoplasm (cytoplasm) where myofibrils are located.
o Ca++ release from sarcoplasmic reticulum causes muscle contraction
o Ca++ uptake and sequestration in sarcoplasmic reticulum causes muscle relaxation

Arrow – at T-tubule
Role of Ca2+ in muscle contraction
- Contraction regulated by Ca2+ release
- Ca++ binding to TnC of Troponin Complex exposes Myosin binding sites on Actin
Role of ATP in movment of Actin along thick filament
 - In absence of ATP myosin head is tightly bound to the actin filament in a rigor state
- Binding of ATP causes slight conformation change myosin dissociates from actin
- ATP hydrolysis  ADP – causes conformation change that displaces mysoin head a short distance along the actin
filament (ADP and Pi remain bound)
- Release of Pi myosin bind to new site on the actin filament generates force for the power stroke.
- ADP release – myosin return to origianl positon causing actin (thin) filament to move (end of cycle)

Muscle Contraction
- A stays – HI goes bye (shortens) as Z- lines move closer together
- During streching - A stays and H and I lengthen (as Z lines move farther apart)

Neuromuscular/ Myoneuronal Junciton: Motor End Plate

- Motor unit – one motor neuron innervationg one or more muscle fibers
- Muscle contraction is all-or-none phenom.
- Synaptic vesicles contain and release acetylcholine, ATP, and proteoglycans
- Acetylcholine receptors are ligand-gated ion channels in sarcolemma
- Also sensory innervation (muscle spindles and Glogi tendon organs)

Summary of Muscle Contraction

1. Motor Axon potential  impulse transmission to muscle cells
2. Depolarization of Sarcolemma
3. T-tubule transmission
4. Opening of Ca2+ channels in SR terminal cisternae
5. Ca2+ release from SR
6. Activation of contractile proteins
7. Reaccumulation of Ca2+ by sarcoplasmic reticulum.

Myotendinous Junctions
- Skeletal muscle is attached to tendon at myotendinous junction. (tendon is attached to bone)
- Collagen fibers of tendon infiltrate and attach to endomysium, perimysium, and epimysium.
- Myofilament movement and myofibril contraction is transferred first to the sarcolemma and then to the
ocnnective tissue sheaths.
- In this way, the conbtractile force fo actin and myosin binding is harnessed for body movement.

Smooth Muscle
- Short, spindle-shaped (fusiform) cells
- Centrally placed nucleus
 - Extensive thin and thick filaments
- Organized as sheets (often 90 degree orientation) or individual cells
- Lack striations, T tubules, or specialized Sarcoplasmic reticulum
- Contraction is not all or none

Smooth Muscle Contraction

- Multi-unit (one nerve fiber innervates single cell – cells can contract independently
- Single- unit (one nerve fiber innervates many cells – cells cannot contranct independently
- Ca++ sources:
o Sarcoplasmic reticulum release
o Calveoli transport – via PM from extracellular fluid
- Thin and thick filaments have some dif. In proteins compared to striated muscle
- Ca++ binds calmodulin resulting in actin-myosin interaction
- Dense bodies
o Present in cytoplasm or cytoplasmic surface of sarcolemma
o Contain a-actinin and other Z disk proteins
o Form framework for a contractile network within cell
- Myofilaments (actin/ myosin) insert into dense bodies
- Intermediate filaments (desmin and vimentin) insert into dense bodies
- Contractgion of myofilaments is relayed to intermediate filaments which twist and shorten the cell

Smooth Muscle Distribution

- Walls of organs (stomach, digestive glands, intestines, lungs, uterus, bladder and more)
-

Digestive System

- Walls of blood vessels

 Artery and Vein

- Dermis of skin (arrector pili muscle)

- Glands (including specialized myoepithelial cells)
- Wounds (specialized myofibroblasts)

Myoepithelial Cells
Cardiac Muscle
- Branched, anastamosing fibers
- Striations same as in skeletal
- Large centrally placed nucleus; usually 1 nucleus
- Specialized end-to-end junctions between cells termed intercalated disks

Arrow at intercalated disk

Distinction of Cardiac from Skeletal Muscle

- Note Branching of Cardiac muscle compared to Skeletal muscle
- Sarcoplasmic reticulum
o Sparse, not as extensive
o Does not form terminal cisternae
o Samll terminals at T tubules
- T- tubules
o Located at the Z disk, not at A-I band junctions
o Lined by external lamina
o Dialted to allow supply of extracellular Ca++
- Additional Ca++ sources due to limited sarcoplasmic membrane system
o Extracellular fluid
o External lamina stores
o Ca++ - Na+ channels
- Intercalated Disks in Cardiac Muscle
o Equivalent of Z disks
o Fascia adherens
o Desmosomes
 - Lateral cell surfaces
o Gap junctions

Specialized Cardiac Muscle Cells

- Some myocytes are specialized fro endocrine secretion of atrial natriuretic peptide (ANP) and other peptides
(i.d. ANP granules in Gartner and Hiatt Fig 8-19)

- Purkinje fibers of the atrioventricular bundle are specialized cardiac myocytes that transmit nerve impulses
within the heart
o Larger than regular cardiac musce
o Fewer myofibrils
o Contain sig. amounts of glycogen

Regeneration of Muscle
- Skeletal muscle
o Myocytes do not have mitotic capability
o Limited tissue regeneration does occur because of satellite cells inside the basal lamina of individual
muscle fibers
- Cardiac muscle
o Myocytes do not have mitotic capability
o The tissue is incapable of regeneration
o In the case of tissue damage such as occurs with a myocardial infarct, fibroblasts invade the damaged
area leading to fibrous connective tissue scar
- Smooth muscle
o Myocytes retain their mitotic capability
o Pericytes in some vessel walls also allow regeneration
o High level of tissue growth or regeneration possible

Additional Clinical Correlations

- Described in Gartner and Hiatt and Burns and Cave textbooks
o Rigor mortis
o Botulism
o Botox injection
o Myasthenia gravis
o Eaton-lambert syndrome
o Muscular dystophies: Duchenne; Becker
o Cardiac Hypertrophy
LAB
- The terms “cell” and “fiber are used interchangeably when referring to skeletal muscle
- Because of the spindle (fusiform) shape of smooth muscle cell, cross sections of smooth muscle will consist of
varying sizes, some containing no nucleus, some containing only a small fraction of the nucleus, and some
containing a large amount of nucleus. This characteristic of smooth muscle will help you to distinguish cross
sections of smooth muscle from other tissues such as peripheral nerve and dense irregular collagen.
- Do not confuse white spaces between skeletal muscle cells and between fasicles with connective tissue
endomysium and perimysium, respectively. These white spaces are not found in living tissue but are artifacts
resulting from preparation of the tissue.

Sample questions

1. The skeletal muscle fiber unit delineated between two Z disks (lines) is termed a:
a. Sarcomere
2. Which of the following is not a characteristic of skeletal muscle
a. Central nuclei and anastamosis
3. The T tubular system consisting of thin surface membrane tubule extending deep into the sarcoplasm and two
lateral extensions of sarcoplasmic reticulum contains
a. High calcium concentration
4. Which of the following is a feature of a white muscle fiber
a. Extensive sarcoplasmic reticulum

Clinical Correlations:

Rigor Mortis
Shortly after the death of an animal, or of a human being, the joints become immoveable. This stiffening of the joints is
referred to as rigor mortis and, depending on the ambient temperature, it may last as long as three days. Because the
dead cells are unable to manufacture ATP, the dissociation of the thick and thin filaments cannot occur, and the myosin
heads will remain bound to the active site of the actin molecule until the muscle begins to decompose. The time of
death may be estimated by the state of rigor mortis, when it is correlated with the record of the ambient temperature
fluctuations. It is interesting to note that the facial muscles are the first to undergo rigor mortis and that the maximal
rigor occurs 12 to 24 hours after death.

Eaton-Lambert syndrome is an autoimmune disease in which autoantibodies to voltage-gated Ca2+ channels in

motoneuron endings inhibit the release of ACh.
- Muscle weakness affects the limbs but usually does not involve the ocular or bulbar muscles. It is often
associated with oat cell (small cell) carcinoma of the lung.

Botulism is usually caused by ingestion of improperly preserved canned foods. The toxin, produced by the microbe
Clostridium botulinum, interferes with the release of acetylcholine, with resultant muscle paralysis and, without
treatment, death.

Myasthenia gravis is an autoimmune disease in which autoantibodies attach to acetylcholine receptors, blocking their
availability to acetylcholine. Receptors thus inactivated are endocytosed and replaced by new receptors, which are also
inactivated by the autoantibodies. Thus, the number of locations for the initiation of muscle depolarization is reduced
and the skeletal muscles (including the diaphragm) weaken gradually. Certain neurotoxins, such as the bungarotoxin of
some poisonous snakes, also bind to acetylcholine receptors, causing paralysis and eventual death due to respiratory
compromise.

Botulinum toxin type A, produced by Clostridium botulinum, is an inhibitor of acetylcholine release by motor fibers that
cause skeletal muscle contraction. For cosmetic purposes, "Botox" is injected into the procerus and corrugator muscles
to diminish the frown lines that the contraction of those facial muscles otherwise produces. By eradicating these
"wrinkles," the face appears smoother and younger looking. In 2001, almost 2 million people were injected with Botox
for cosmetic purposes. The effect lasts for less than 3 months, and many patients repeat the procedure two to three
times per year. There appear to be no serious side effects, but if injected into the wrong muscles, ptosis of the eyelids
could persist for several months. Occasionally individuals suffer headaches, cold-like symptoms, and nausea, as well as
muscle weakness, pain, and inflammation in the area of the injection for as long as 4 months.

The simple reflex arc, such as the knee jerk, is an example of the function of muscle spindles. Tapping on the patellar
tendon results in a sudden stretching of the muscle (and of the muscle spindles). The primary and secondary nerve
endings are stimulated, relaying the stimulus to the γ-motor neurons of the spinal cord, resulting in muscle contraction.

The ability of a person to touch his or her nose in absolute darkness is due to the integrative activities of muscle spindles
and, possibly, to Golgi tendon organs. These structures provide not only feedback about the amount of tension placed
on the muscle and tendon but also input to the cerebellum and cerebral cortex supplying information about the body's
position in three-dimensional space; this ability is referred to as proprioception.

During cardiac hypertrophy, the number of myocardial fibers is not increased; instead, the cardiac muscle cells become
longer and larger in diameter. Damage to the heart does not result in regeneration of muscle tissue; instead, the dead
muscle cells are replaced by fibrous connective tissue.
Lack of Ca2+ in the extracellular compartment results in cessation of cardiac muscle contraction within 1 minute, whereas
skeletal muscle fibers can continue to contract for several hours.
Although a small amount of energy production may be achieved by anaerobic metabolism (up to 10% during hypoxia),
totally anaerobic conditions cannot sustain ventricular contraction.

Muscular Dystrophies

Duchenne muscular dystrophy (DMD)

- X-linked (dystrophin gene mutated)-
- Early onset Usually fatal by maturity
- Progressive weakness of pelvic and limb girdles
- (Early Gowers' sign)
- Extensive pseudohypertrophy of calf muscles (replacement of lost fibers by connective tissue and fat)
- Swaying gait, with legs kept wide apart
- Cardiac involvement

Becker muscular dystrophy

- X-linked (dystrophin gene mutated
- Late onset
- Slow progression
- Similar to DMD, but less severe

Myotonic muscular dystrophy

- Autosomal dominant
- Childhood onset common but may be later - Slow progression
- Sustained muscle contraction (myotonia), especially in face and neck, followed by muscle atrophy
- Distinctive ring fibers
- Cataracts, gonadal atrophy, frontal balding, cardiac defects
MA Study Guide Test 2 - PNS
Lecture PNS – Stanley
Nervous Tissue

- input (Sensory)
- output (Motor)
- Functional Unit: PERIPHERAL NERVES (Cranial and Spinal Nerves)

PNS
- Neurons located outside the brain and spinal cord (CNS)
- Input/output system
- Nerves and Ganglia
- Neural crest cells derived from neuroectoderm give rise to the PNS.

PNS Functional Divisions

- Somatic NS (body, e.g. muscles, skin)

o Sensory to CNS
o Motor from CNS (just one neuron)
- Autonomic NS (visceral e.g. gut, heart) – some glands, cardiac muscle and involuntary smooth muscle.
o Motor from CNS = 1st neuron
o From Ganglion = 2nd neuron
o Parasympathetic (rest and digest) – 1st neuron in the cranial or sacral region of spinal cord – 2nd
neuron in or near the organ they innervate
o Sympathetic – (fright or flight/) – 1st neuron in thoracic or lumbar region of spinal cord – 2nd
neuron in sympathetic ganglia near the spinal cord

PNS Structural Components

- A peripheral nerve comprises bundles (fascicles) of nerve fibers (axons) that are surrounded by myelin
sheaths or Schwann cells and are invested with three connective tissue elements.
- Contain both Motor and Sensory Axons (two way street)
- Ventral Horn of spinal cord – Gray Matter – motor neurons sending out impulse
- Dorsal Root Ganglion (DRG) receive sensory input and transmits it to the spinal cord.

Connective Tissue elements

- Epineruium – thick fibrous coat that forms the external covering of a nerve
o Blood and lymphatic vessels
o Adipose
o Loose connective tissue
- Perineurium – layer of dense connective tissue around each fascicle of nerve fibers
o Inner surface lined with epithelial-like cells joined by Zonulae Occludens (tight junctions) –
provide permeability barrier.
- Endoneurium: - thin loose reticular layer (collagen type III)
o surrounds each individual Axon
o contains Schwann cells
- Connective Tissue Sheaths made by Fibroblasts
Schematic depiction of a typical reflex arc, with a cross-sectional view of mixed peripheral nerve. Note the
bundles (fascicles) of fibers in the nerve and the three types of connective tissue layers. Stimulation of sensory
nerve endings in the skin triggers an impulse that is transmitted to the spinal cord via the dorsal root ganglion.
The sensory impulse is transmitted to a motor neuron (via an interneuron), triggering a motor impulse that
passes to a skeletal muscle. The knee-jerk reflex and the heat-induced withdrawal reflex operate in this fashion.

Location of neurons (Whose Axons form Peripheral Nerves

- Cranial Nerves
o Motor Nuclei – in brainstem
o Sensory Ganglia – in brain stem
- Spinal Nerves
o Motor Nuclei – in Gray Matter (Ventral Horn of Spinal Cord)
o Sensory Ganglia (DRG)

TWO WAY STREETS

- Spinal Reflex Pathway (spinal nerves)

o Country Road – reflex arc described above
- Autonomic Reflex Pathway (Autonomic Nerves
o Much more complex (only briefly discussed)

PNS Cells
 - Neurons (FPMs)
- Glial Cells
- Vascular Cells
- Fibroblasts

Neurons: 3 Basic Types (based on Morphology and Function

1. Pseudounipolar - single axon extending divides into two branches, one functioning as an axon and the
other as a dendrite
a. General Sensory (receptor endings vary)
b. Found in the sensory ganglion of brain stem and DRG near spinal cord.
c. Note: very round cell – central nucleus – prominent nucleolus and encircled by satellite cells

2. Bipolar – Special Sensory (Neuroscience course)

3. Multipolar – have multiple dendrites and a single axon, are the most abundant.
a. Motor
i. Somatic (skeletal muscdle)
1. Body found in Ventral Horn of Spinal Cord
ii. Autonomic (Smooth Muscle)
1. Body found in Lateral Horn of Spinal Cord
2. Body found in Autonomic Ganglia (Chain, Cranial or in Organs)
3. Note: Eccentric nucleus, prominent nucleolus – only partially circled by Satellite
cells.
Parts of a Neuron

- Cell Body – Perikaryon – Encircles Nucleus

o Typical Organelles
o Low glycogen – no storage – CV system favors brain to provide constant energy.
o NISSL Substance (not in axon hillock) – Composed of RER and free ribosomes (note: stacks of
RER in figure below)
 o Lipofuscn granules (cellular inclusion) lysosomal debris – increase in number with age. (Stained
in figure below – look like trash – do not confuse with NISSL in figure above.

o FPMs (so Centrioles are vestigial)

o Surface
 Synapses
 Astrocytic feet (CNS)
 Myelin (Axon only)
- Nucleus – Karyon
o Euchromatin (active)
o Prominent Nucleolus
- Fibers – Processes
o Axons – send info.
o Dendrites – receive info

Axon (send info)

- Functions
- Hillock (initial Segment)
- Myelination
- Collaterals
- Terminal (Bouton, End Bulb)
- Synapse

Two Function of Axon

- Conduction (Electrical)
o Action Potention
o Votage Gated Na+ Channels
o Axon Hillock (origin)
 o One Direction (toward Synapse)
- Transport (Mechanical):
o Synaptic Vesicles
o Microtubules
o Two Directions
 Anterograde (toward synapse – kinesin)
 Retrograde (toward cell body (dynein)
Axon Hillock (Initial Segment)
- No Nissle
- Many Synapses
- Most Excitable
- After Hillock – axon narrows and myelination begins
-

Na+ Channels (Shown with Immunohistochemistry)

- Most concentrated at:
o Initial Segment
o Nodes of Ranvier
Myelination of Axons
- Specific Glial Cells Make Myelin:
o CNS – Oligodendrocyte (Many Axons, Octapus) – White Matter
o PNS – Schwann Cell (One Axon, Hot Dog Bun) – White Nerves
- Composition of Myelin
o 80% Lipid
o 20% Protein
 Myelin Basic protein (MBP)
 Myelin Oligodendrocyte Glycoprotein (MOG) and Proteolipid Protein (PLP)
- Function: (Saltatory Conduction)
o Increases speed of Nerve Impulse – nerve impulse jump between nodes of Ranvier
o Also increase speed the larger the diameter of Axon – more myelin.

Process of Myelination
- Schwann Perikaryon Extends
- Neuregulin protein – attracts Schwann Cell to Axon
- + 50 Circles
o Internal Mesaxon (first wrap)
o External Mesaxon (last wrap)
- Cytoplasm Squeezed (toward nucleus)
- Surfaces Approximate
o Cytoplasmic - Major Dense Line – seen in top left of right figure below – dark line
o External: - Intraperiod Line – seen in top left of right figure below – light spot between dark
lines.
- Schwann Cell
o Myelinates ONE Axon
o Takes Care of many unmyelinated Axons
o Note the Myelinated Axons and Unmyelinated Axons in right figure below.
Dentrite/Axon Endings

- Sensory Endings
o Pacinian Corpuscle (Deep touch, vibration – deep to surface)
 Prevalent in dermis and hypodermis of the skin

o Meissner’s Corpuscle (light touch – close to surface)

 Prevalent in superficial dermis of the palms, soles, external genitalia, nipple, and lips.
 Note the darkly stained epidermis and lighter stained dermis surrounding.
 o Golgi Tendon Organ (info about how hard tendon pull on bone – protect tendon attachment)
o Muscle Spindle Organ (football in muscle – run parallel with muscle cells – keep constant slight
tension so you don’t have to expend large amount of ATP to use a muscle from rest.
- Motor Endings
o Neuromuscular Junciton

Synapse

- Types
o Chemical (Neurotransmitter)
o Electrical (Gap junction)
- Anatomy
o Presynaptic density – vesicles released (require Ca++)
 Synapsin I Clusters Vesicles
o Synaptic cleft 10-20 nm
o Postsynaptic density – RECEPTORS
Types of Synapses by location
- Axosomatic (axon to cell body)
- Axodendritic
- Axoaxonic
- Response Depends on RECEPTOR

Neuromuscular Junction (at end bulb)

- Chemical Synapse (uses Ach)
- Junctional folds – very important for identifying NM junction – post junctional folds on the Sarcolema
of muscle cells.
- Myasthenia Gravis (Antibodies to Ach receptors – muscle weakness)

2 Ways Axons Branch

- Collater Branch
- Terminal Arborization – End in end bulb to skeletal muscle.
Dendrites (info TO cell body)
- Synapses
o Axodendritic
o Dendodendtitic (rare)
- Arborization (branches like tree)
- Spines (decrease with Age and Disease)
- EM Structures:
o Mitochondria, Microtubules (not in spines)
o Neurofilaments, SER
o NISSL (unlike Axon
o No Golgi

Dendrite or Axon
 - Arrow pointing to synapse
- Axon has synaptic vesicles.

Regeneration of Axons (Role of Glia)

- PNS – Schwann cells (HELP Regeneration)
- CNS – Astrocytes (Prevent regeneration via Scar
o Glial Scar = Glial Fibrillary Acidic Protein (GFAP) + Astrocytes

Axonal Response to Injury

- Pathological Changes
o At injury Site
o Distal Reaction
 Wallerian Degeneration or (Anterograde Reaction, down Axon)
o Proximal
 Central Chromatolysis (Retrograde Reaction toward Cell body) – because nissal
substance in neuron disperse and break up
Regeneration (PNS not CNS)
- Depends on:
o Schwann Cell  BASAL LAMINA
o Schwann Cell  Endoneurial Tube
- Growth approx. 3-4 mm/day
Vascular Barriers (Endothelial Cell Zonula Occludens)
- Blood Nerve Barrier (PNS)
o Perineurium / Endothelium (Capillary)
o Leaky = Nerve Edema (e.g. Diabetic POlyneuropathy) – toxic to nerves
- Blood Brain Barrier (CNS)
o Brain Parenchyma / Endothelium (Capillary)
o Leaky = Vasogenic Edema (e.g. Brain Tumor)

Neurohistologic Methods
- Stains
o Hematoxylin (stains acids – blue) and Eosin (stains bases- red)
o Nissl Stain
o Silver
 Golgi
 Cajal
 Hortega
o For Lipids (stain myelin very densly)
 Weigert
 Osmium Tetroxide
- Immunohistochemistry
o Specific Antibodies to Neurotransmitters or Proteins
- Pathway Tacing
o Anterograde Transport (toward synapse)
o Retrograde Transport (toward cell body)

Sample Questions
 1. Your adolescent patient present with restlessness, malaise, and fever a few days after suffering a dog
bite on the hand. Restlessness increases in a few days to uncontrollable excitement with excessive
salivation and painful spasms of the laryngeal muscles. You suspect early stages of rabies, and from
your training you remember that the rabies virus can be transported retrogradely through peripheral
nerves to reach the spinal cord and brain. What would be the mechanism by which the virus affects
salivary glands and laryngeal muscles?
a. Anterograde transport in axons of CNS neurons to glands and muscles
2. Which of the following is characteristic of a multipolar neuron whose axon forms part of a splanchnic
nerve?
a. The perikaryon is located in the spinal cord.
3. The _____ has an important role in regeneration of axons in the PNS. By contrast, the _____, a GFAP
positive, scar forming cell, limits regeneration of axons in the CNS.
a. Schwann cell / Astrocyte

LAB: PNS

- Difference b/t (X) and (L) sections of smooth muscle vs. (X) and (L) sections of peripheral nerve.
o Peripheral nerve is wavy in (L) section.
o Sometimes looks like “crushed ice” in (X) section
o Axons appear relatively uniform in sizxe in shape in X section where smooth muscle clls vary in
size.
o No nuclei are found within axons whereax smooth muscle cells have centrally located nuclei.
- Satelite cells around dorsal root ganglia (DRG) neurons are more organized than satellite cells around
autonomic ganglia neurons because of the round shape and single process of pseudounipolar DDRG
neurons as opposed to the oval shape and multiple processes of multipolar autonomic ganglia neurons.
DRG neurons typically have an abundance of lipofuscin pigment.
- Myenteric plexus (Auerbach’s) b/t longitudinally and circularly arranged layers of smooth muscle. T
- The submucosal plexus (Meissner’s) is surrounded by loose collagen.
- Neurokeratin is a protein artifact of fixation
- The neurolemma consist of the PM of the Schwann cell, not the neuron.
- Neurons usually have prominent nucleoli within their nuclei.
- Purkinje, pyramidal, and alpha motor neurons are the largest neurons in the CNS
- Purkinje neurons are found in the cerebellum, pyramidal neurons in the cerebrum, and alpha motor
neurons in spinal cord.
- Granule cell neurons are very small (some < diameter of an RBC) with very scanty cytoplasm. They are
best seen in the cerebellum where million of them comprise the ganule cell layer.
- Astrocytes have very large numbers of processes (arms) that arise from their cell bodies. They are best
seen with silver stains or with immunohistochemical markers. In H and E and cresyl violet stained
tissue, usually only the nuclei are visible.

Clinical Correlations:

Abnormal organogenesis of the CNS results in various types of congenital

malformations. Spina bifida is a defective closure of the spinal column. In severe cases,
the spinal cord and meninges may protrude through the unfused areas. Spina bifida
anterior is a defective closure of the vertebrae. Severe cases may be associated with
defective development of the viscera of the thorax and abdomen.

Anencephaly is failure of the developmental anterior neuropore to close, with a poorly

formed brain and absence of the cranial vault. It usually is not compatible with life.
 Epilepsy may result from abnormal migration of cortical cells, which disrupts normal
interneuronal functioning.

Hirschsprung disease, also known as congenital megacolon, is caused by failure of the

neural crest cells to invade the wall of the gut. The wall lacks Auerbach's plexus, a
portion of the parasympathetic system innervating the distal end of the colon. Absence of
the plexus leads to dilatation and hypertrophy of the colon.

Retrograde axonal transport is used by certain viruses (e.g., herpes simplex and rabies virus) to spread from one neuron
to the next in a chain of neurons. It is also the method whereby toxins (e.g., tetanus) are transported from the periphery
into the CNS.

Although neurological tumors account for about 50% of intracranial tumors, those of neurons of the CNS are rare. Most
intracranial tumors originate from neuroglial cells (e.g., benign oligodendrogliomas and fatal malignant astrocytomas).
Tumors that arise from cells of connective tissue associated with nervous tissue (e.g., benign fibroma or malignant
sarcoma) are connective tissue tumors and are not related to the nervous system. Tumors of neurons in the PNS may be
extremely malignant (e.g., neuroblastoma in the suprarenal gland, which attacks mostly infants and young children).

Large populations of microglial cells are present in the brains of patients with acquired immunodeficiency syndrome
(AIDS) and human immunodeficiency virus-1 (HIV-1). Although HIV-1 does not attack neurons, it does attack microglial
cells, which then produce cytokines that are toxic to neurons.

Multiple sclerosis (MS), a relatively common disease affecting myelin, is 1.5 times more common in females than in
males. It usually occurs between 15 and 45 years of age, and its principal pathological feature is demyelination in the
CNS (optic nerve, cerebellum, and white matter of the cerebrum, spinal cord, and cranial and spinal nerves). The disease
is distinguished by episodes of random, multifocal inflammation, edema, and subsequent demyelination of axons in the
CNS, followed by periods of remission that may last for several months to decades. Each episode may further jeopardize
the patient's vitality. Any single episode of demyelination may cause deterioration or malignancy of the affected nerves
and may lead to death in a matter of months. Because this demyelination is thought to result from an autoimmune
disease with inflammatory features (which may manifest as a possible aftermath of an infectious agent),
immunosuppression with corticosteroids is the most common therapy for multiple sclerosis, although the anti-
inflammatory activity of the therapy is thought to be most beneficial.

Radiation therapy can lead to demyelination of the brain or spinal cord when these structures are in the radiation field
during therapy. Toxic agents, such as those used in chemotherapy for cancer, may also lead to demyelination, resulting
in neurological problems.

Guillain-Barré Syndrome is an immune disorder that produces inflammation and rapid demyelination within the
peripheral nerves and the motor nerves arising from the ventral roots. This disease is associated with recent respiratory
and/or gastrointestional infection. A symptom of this disease is muscle weakness in the extremities, reaching a high
point within just a few weeks. Early recognition is followed by physical therapy and respiratory and autoimmune
globulin treatments.

Huntington's chorea is a hereditary condition with an onset in the third or fourth decade of life. It begins as flicking of
the joints that progresses to severe distortions, dementia, and motor dysfunction. The condition is thought to be related
to loss of cells producing GABA, an inhibitory neurotransmitter. Without it, outbursts are uncontrolled. The dementia
associated with this disease is thought to be related to subsequent loss of acetylcholine-secreting cells.

Parkinson's disease, a crippling disease related to the absence of dopamine in certain regions of the brain, is
characterized by muscular rigidity, constant tremor, bradykinesia (slow movement), and, finally, a mask-like face and
difficult voluntary movement. Because dopamine cannot cross the blood-brain barrier, therapy is administered as L-dopa
(levodopa), which relieves the motor abnormalities temporarily, although the neurons in the affected area continue to
die. Efforts to transplant fetal adrenal gland tissue into persons with this disease have provided only transient relief. The
therapeutic grafting of genetically modified cells capable of secreting dopamine will perhaps allow the establishment of
synaptic connections to cells in the corpus striatum of the brain where dopamine is needed.
MA Study Guide Test 2 – Bone and Cartilage

Bone (osteo)
- Vascular
- Mesodermal origin (from mesenchyme)
- Cells Matrix
- Osteoblasts
- Osteocytes
- Osteoclasts
- Periosteum
- Collagen Type I
- Appositional growth (on the surface)
- Compact, Cancellous, Woven (young bone or new bone – compact, or cancellous)
Cartilage (chondro)
- Avascular (requires diffusion)
- Mesodermal origin
- Cells and matrix
- Chondroblasts
- Chrondrocytes
- There are no condroclasts (doesn’t get broken down)
- Perichondrium (except articular cartilage and fibrocartilage – don’t have nerves or blood vessels)
- Collagen types I and II
- Appositional growth
- Interstitial growth (from within)
- Hyaline, Elastic, Fibrocartilage

Bone

- Medullary cavity – bone marrow cavity – in center of bone

- Cortical bone – on the outside – compact bone

Cancellous Bone
o Spongy Bone
o Spicules (peninsula of bone) and tribeculum (net)
 Lined by endosteum (prpogenitors, blasts, clasts)
 Bone marrow between
 Avascular (nutrients diffuse)
o No Osteons
o Irregular Lamellae
o Bounds Epiphyseal Plate
 HistoTime

Note (middle) specs of BM in white spaces between spicules

Compact (lamella in circles or long lines – just means a sheet (H and C)

3 Cell types in bone

1. OsteoBLAST (mesenchyme) – make

- Tend to be cuboid shape – lineing spicules once they are trapped in bone become osteocytes  holes called
lacunae (both from mesenchyme)
- From:
o Mesenchyme
o Endosteum (inside the marrow cavity)
o Periosteum (outside the bone)
- Character:
o Stellate (star shapped – unlike round chondroblasts)
o Basophilic (RER – protein – stain eosin)
- Funciton:
o Stimulate osteoclasts (via factos)
o Make Bone:
 Matrix Proteins
 Type I collagen (90% of protein)
 Glycoproteins
 Proteoglycans
 Alkaline Phosphatase
 Secretes Osteoid (on pre-existing surfaces – apostitioanlly ) – fresh bone
 RER
 Prominent golgi (collagen precursors)
 Need Vit. C (to hydroxylate proline in collagen)
 Become osteocytes
Bone Matrix Proteins (basically adhesive glycoproteins – bind something)
- Osteocalcin
 o Binds calcium (hydroxyapatite)
o Attracts osteoclasts
o Increased in urine in dz. (Pagets, Hyperparathyroid and Renal Osteodystrophy)
- Osteopontin
o Binds integrings
o Osteoclasts to bone
- Osteonectin
o Binds calcium
o Minerals to collagen
Paget’s – osteitis deformans – remodeling disorder – intense osteoclast resorption + vigorous osteoblast activity

Renal Osteodystrophy - chronic kidney failure – decreased excretion of phosphate (hyperphosphatemis) + low serum
calcium (hypocalcemia

(collagen fibrils in osteoid – Process Trapped (arrow)

2. Osteocyte (mesenchyme) – adult

- From:
o Osteoblasts (mesenchyme)
- Character:
o In lacunae
o Processes in Canaliculi (Gap junctions)
 Canaliculi – small canals that the processes of osteocytes travel through and connect with others
to form gap junctions
o Periosteocytic Space (Calcium resorption – small amount)
o not very active (small Golgi and RER)
o Nondividing (NO interstitial growth)
- Function
o Osteocytic Osteolysis (regulates Plasma Ca++) by osteocyte in periosteocytic space
o Mechanotransduction (pull or push, recruit preosteoblasts)
  make bone due to working out – like muscle.

(blood vessels would go through the center – also go through canaliculi and lacunae)

(osteocyte)

3. Osteoclast (GM-CFU) – breakdown

a. GM-CFU (granulcyte monocyte colonly forming unit
b. Sits in resorption bay
c. Eventually creates a resorption tunnel in bone
- From:
o Hematopoetic Stem Cells (Bone Marrow GM-CFU)
o ???Endoreduplication (duplicated nuclei in cell with no divion of cytoplasm) or Fusion of Monocytes???
- Character:
o Large, motile, multinucleated, acidophilic
o Howships lacuna where they live – can create a resorption tunnel
o Ruffled border
o ‘Clear Zone’ (No organelles, Actin Ring = Seal)
 Actin microfilaments that form actin ring to keep plasma membrane in contact with bone –
sealing zone
o Integrins (low- affinity receptors) to attach to bone – but also allow movement
o Many Mitochondria, Golgi, Lysosomes, RER
o Nondividing
- Function – Resorb Bone (mineral first then collagen and other protein)
- Notes:
o OPGL – facilitates formation of actin ring and osteoclast mitosis
o OPG – suppresses osteoclast activity and inhibits differentiation
o Mineral Dissolution (acid digest Ca out of bone)
 Outside ruffled border
 Lysomal enzymes + acid environment
 Low pH:
o Na+/H+ exchange (active transport)
o Proton Pumps (need ATP)
o Carbonic Acid (H2CO3) (dissociates into H+ ions via Carbonic Anhydrase)
o Collagen Degradation
 Lysosomal Enzymes:
  TRAP (Tartate Resistant isoenzyme of Acid phosphatase, marker for finding osteoclast)
 Cystein – Proteinases, e.g. Cathepsins

(see osteoclast with multiple nuclei sitting in resorption bay) (H – Howship’s Lacuna (resorption bay)

Ruffled Border

(left) Osteoblast on top – Osteoclast on bottom – arrow heads in oval = hydroxyapatite being digested at ruffled border)
– MF – mineralization front – RF – resorption front
(right) note ruffled border and resorbing bone matrix at bottom

Compact Bone (terminology)

- Periosteum
o Lines exterior of bone
o 2 layers
 Fibrous (outer- has blood vesels and nerve
 Osteogenic (inner – has cells that make bone cells)
- Endosteum (inside bone
o Osteoprogenitores (bone pre-cells)
o Blasts
o Clasts (from GM-CFU)
o Lines marrow cavity and haversian canals
- Haversian System (osteon) – smallest functional unit of bone – series of concentric or circ. Lameellae
- Interstitial Lamellae (oldest bone, osteon pieces)
o Haversian system left after osteoclast come and made tunnel
(left) – Note Osteon = haversian system – Periosteum  circumfrential lamellae  osteon  haversian canal
(connected through volkmans canals)
(Right) Note: Outer circumfrential lamellae (note collagen fibers arranged at 90 deg. To eachother to provide support. –
inner circumfrential lamellae

Microanatomy of an Osteon
- Haversian Canal
o Blood vessels and nerves
o Lined by endosteum (osteoprogenitor cells)
- Cement Line
o Outermost boundary of osteon
o Lacks canaliculi
- Concentric Lamellae
o Older = Cement Line
o Lacunae (osteocytes)
o Canaliculi (processes, Gap junctions)
- Osteons
o Grow in resorption tunnel (opposite to tree – youngest concentric lamellae is around the haversian
canal

Note: Interstitial lamellae (oldest bone  peaces left by clast) – Osteon on the left is younger ( less rings near canal)

Microvascular System of Bone

- Blood Supply 4 Sources:

o Nutrient Arteris (nutrient foramina in shaft)
o Periosteal System
o Metaphyseal System
o Epiphyseal System
 - Arterial Supply of Cortex (centrifugal)
o Inside to out
- Venous flow (centripetal)
o Cortical Capillaries  Venous Sinusoids  Emissary Veins

Note: Metaphyseal artery- Epiphyseal Artery – Periostal Artery (from outside or inside the bone)

Volkmann’s Canal

Vascular Content of Haversian Canal

Periosteum
- Connective Tissue (covers Bone)
o Active in Children (bone diameter growth)
o Resting in adults
- 2 Layers:
o Inner Cellular Layer:
 Osteoprogenitor cells (for bone repair)
 o Outer Fibrous Layer
 Dense Fibrous Connective Tissue
 Contiguous with joint capsules

Active Periosteum

Note: Osteoprogenitor Cell Layer (O) is thick. – From developing fetal long bone. Osteoblasts (basophilic RER) – loose
collagenous tissue - C= fibrous layer.

Mature Periosteum

Note: Osteoprogenitor Cell layer THIN (indistingushable from fibroblast) – differentiate during growth or repair.
Appositional growth.
(right) collagen fibrous layer stained blue.

Sharpeys Fibers (periosteum to bone) – thick collagen fibers – Very Important!!!

Cartilage
- Appositional + interstitial growth
- Perichondrium (not articular and fibrocartilage
o Outer fibrous layer (type 1 collagen)
o Inner chondrogenic layer (appositional growth)
o Chondroblasts + Chondrocytes
o Matrix
 GAGs (Attract Na+, H2O – resists compression
 Territorial (Capsular) Matrix
 GAG’s!!! = Basophilic (near the cells)
 Borders Lacunae
 Interterriotorial Matrix
 Fewer GAG’s = Less Basophilic
o Avascular (diffusion and Joint mice (Small fibrous, cartilaginous, or bony loose bodies in the synovial
cavity of a joint.

Cartilage Cells
- Chondroblasts (in chondrification centers)
o From
 Stellate Mesenchyme (become round)
 Perichondrium (chondrogenic layer)
o Secrete Mattrix (vesicles)
o Basophilic (abundant RER)
- Chondrocytes
o Can Divide – also making cartilage – dif than bone (why we get interstitial growth)
o Trapped in lacunae (round)
o Secrete matix
o Older = less active
o Can revert to chondroblasts
o Isogenous groups (CELL DIVISION, Interstitial growth)

Hyaline Cartilage
- “Glassy Matrix (Greek, Hyalos = glassy)
o Type II Collagen
o Ground Substance
 Aggregans (chondroitin Sulfate + Heparan Sulfate)
 Chondronectin (binds collagen, GAGs and Integrins)
- Perichondrium (NOT on articular hyaline cartilage!!!)
- Isogenous Groups (NESTS)
o Sister Chondrocytes (separate Lacuna)
o Cell division (interstitial growth)
- Endochondral Bone Formation
- Calcifies (normal aging)
- Located in:
o Embryonic Skeleton
o Epiphyseal Plate
o Articular Cartilage
o Nasal Cartilages
o Tracheal Ring
Note: (left) very glassy  could ice skate on them. (Right) Terriotory Matrix (dark purple, arrow) = many GAGs

Articular Cartilage (Hyaline)

Synovial Membrane
- Makes synovial fluid (Type B cell)
- Not a true epithelium
o Discontinuous – no basement membrane

Elastic Cartilage
- Matrix
o Elastic Fibers > Type II Collagen
o Ground Substance
 Aggregancs (chondroitin Sulfate and Heparan Sulfate)
 Chondronectin
- Perichondrium
o Outer Fibrous Layer Elastic Fibers
- Isogenous Groups
o Clustered Chondrocytes (separate lacuna)
o Cell division
o # chondrocytes > # in hyaline
o Large Elastic Fibers in Territoral Matrix (special stain)
- Located in:
o Pinna (of ear)
 o Epiglottis

Note: a lot more cells – can’t ice skate on this

Fibrocartilage
- Matrix
o Type I collagen (acidophilic)
o Ground Substance
 Chondroitin Sulfate and Dermatan Sulfate
- No Perichondrium
- Chondrocytes
o Fewer than Fibers (“fibro” cartilage)
o From fibroblasts
o Isogenous ROWS
- Located in:
o Intervertebral Disks
o Pubic Symphysis
o Menisci

Note: NP – nucleous pulpus in IV disk – remenant of the fetal notochord – the part that herniates

Sample Questions:

1. Which of the following is characteristic of adult hyaline cartilage?

a. Appositional growth (and interstitial growth for all cartilage)
2. Production of osteoid could be impaired by
a. Osteoprogenitor cells not differentiating

Clinical Correlations:
BONE DISORDERS
 Osteogenesis imperfecta: a group of diseases caused by mutation in a gene encoding one
of the α chains of type I collagen, leading to a disturbance in the amount and quality of
bone collagen. It is marked by fragile bones that are prone to fracture, lax joints, and
discolored teeth. Characteristic blue sclerae result from thinning of the sclerae and
increased visibility of the underlying choroidal veins. The most common and mildest
form (type I) exhibits autosomal dominant transmission.

Osteopetrosis: a hereditary disease characterized by abnormally dense bone usually due

to decreased resorption by dysfunctional osteoclasts. The most severe form (autosomal
recessive), occurring in infancy and childhood, leads to obliteration of marrow cavity and
lack of bone remodeling. Bone fractures, anemia, and cranial nerve palsies (bone
entrapment) are common complications. Bone marrow transplants have been helpful.

Osteoporosis: a metabolic disorder characterized by decreased bone mass caused by an

imbalance between bone formation (decreased) and bone resorption (increased). All
forms are associated with increased risk of fracture after minor trauma and may cause
pain (especially in the lower back), loss of body height (compression vertebral fractures),
and deformities.

 Postmenopausal osteoporosis, occurring in women 3 to 20 years after menopause,

results from excessive bone resorption by osteoclasts. A lowered estrogen level in
postmenopausal women is a risk factor because estrogen inhibits osteoclast-
activating factor.
 Senile osteoporosis, occurring in both men and women older than age 70 years,
results from decreased bone formation by osteoblasts.
 Immobilization, endocrine disorders (e.g., hyperparathyroidism), and other
diseases also can cause osteoporosis.

Paget's disease of bone (osteitis deformans): a chronic, often asymptomatic bone

disorder that occurs primarily in individuals older than 40 years. Repeated episodes of
increased osteoclastic activity, followed by excessive attempts at repair (osteoblastic
activity), result in weakened, thickened bones, called mosaic bone. Bowing of long
bones, spinal curvature (kyphosis), bone pain, and multiple fractures are common
manifestations.

Osteosarcoma (osteogenic sarcoma): the second most common malignant tumor of

bone origin, mainly affects young males. It generally involves the metaphysis of the
distal femur or proximal tibia and often spreads to the lungs. Tumors are highly variable
and are classified based on their major histologic component.

Joint disorders

1. Osteoarthritis: a noninflammatory, degenerative disease that commonly affects the joints of the hand,
cervical and lumbar spine, hip, and knee
o Pathologic changes include degeneration of the articular cartilage, thickening and polishing of
subchondral bone (eburnation), and formation of bony spurs (osteophytes) that often extend into
the joint.
2. Rheumatoid arthritis: chronic inflammatory arthritis caused by autoimmune mechanisms and involving
systemic effects
 o Inflammation and proliferation of the synovial membrane lead to the formation of a rheumatoid
pannus, the characteristic joint lesion. Muscle atrophy and ankylosis occur at later stages.
3. Ankylosing spondylitis: a chronic degenerative inflammatory disease that primarily affects males
younger than age 30 years and initially involves the spine
o Marked by synovitis without pannus formation and inflammation of ligaments at their insertion
into bone; may progress to ankylosis of the spinal column
o Often associated with inflammatory intestinal diseases

Gartner and Hiatt

Hyaline cartilage degenerates when the chondrocytes hypertrophy and die and the matrix begins to calcify. This process
is a normal and integral part of endochondral bone formation; however, it is also a natural process of aging, often
resulting in less mobility and in joint pain.

Cartilage regeneration is usually poor except in children. Chondrogenic cells from the perichondrium enter the defect
and form new cartilage. If the defect is large, the cells form dense connective tissue to repair the scar.

A ruptured disk refers to a tear or break in the laminae of the annulus fibrosus through which the gel-like nucleus
pulposus extrudes. This condition occurs more often on the posterior portions of the intervertebral disks, particularly in
the lumbar portion of the back, where the disk may dislocate, or slip. A "slipped disk" leads to severe, intense pain in the
lower back and extremities as the displaced disk compresses the lower spinal nerves.

Osteoblast cell membranes are rich in the enzyme alkaline phosphatase. During active bone formation, these cells
secrete high levels of alkaline phosphatase, elevating the levels of this enzyme in the blood. Thus, the clinician can
monitor bone formation by measuring the blood alkaline phosphatase level.

Osteopetrosis, not to be confused with osteoporosis, is a genetic disorder where osteoclasts do not possess a ruffled
border. Consequently, these osteoclasts cannot resorb bone and persons with osteopetrosis display increased bone
density. Individuals suffering from this disease may exhibit anemia resulting from decreased marrow space, as well as
blindness, deafness, and cranial nerve involvement because of impingement of the nerves due to narrowing of the
foramina.

If segments of bone are lost or damaged so severely that they have to be removed, a "bony union" is not possible; that
is, the process of bone repair cannot occur because a bony callus does not form. In cases of this sort, a bone graft is
required. Since the 1970s, bone banks have become available to supply viable bone for grafting purposes. The bone
fragments are harvested and frozen to preserve their osteogenic potential and are then utilized as transplants by
orthopedic surgeons. Autografts are the most successful because the transplant recipient is also the donor. Homografts
are from different individuals of the same species and may be rejected because of immunological response.
Heterografts, grafts from different species, are least successful, although it has been shown that calf bone loses some of
its antigenicity after being refrigerated, making it a worthy bone graft when necessary.

Acromegaly occurs in adults who produce an excess of somatotropin, causing an abnormal increase in bone deposition
without normal bone resorption. This condition creates thickening of the bones, especially those of the face, in addition
to disfiguring soft tissue.

Rickets is a disease in infants and children who are deficient in vitamin D. Without vitamin D, the intestinal mucosa
cannot absorb calcium even though there may be adequate dietary intake. This results in disturbances in ossification of
the epiphyseal cartilages and disorientation of the cells at the metaphysis, giving rise to poorly calcified bone matrix.
Children with rickets display deformed bones, particularly in the legs, simply because the bones cannot bear their
weight.

Osteomalacia, or adult rickets, results from prolonged deficiency of vitamin D. When this occurs, the newly formed bone
in the process of remodeling does not calcify properly. This condition may become severe during pregnancy because the
fetus requires calcium, which must be supplied by the mother.

Scurvy is a condition resulting from a deficiency of vitamin C. One effect is deficient collagen production, causing a
reduction in formation of bone matrix and bone development. Healing is also delayed.
MA Study Guide Test 2 – Bone Development

Endochondral Ossification
- Bones:
o Long Bone
o Vertebrae
o Pelvis
o Base of Skull
- Hylaine Cartilage Model (interstitial and appositional growth model)
- Vascularize Perichondrium (chondrogenic cells become osteogenic cells)
o Boney Collar (intramembranous) formed
 Chondrocytes hypertrophy and Die (release alk phosphatase)  Calcify Cartilage
- Periorsteal Vascular Bud (osteoclasts eat through bony collar)
o Carries in osteoprogenitor cells and blood vessels and hematopoetic cells
o Primary Center of Ossification
- Osteoblasts Make Osteoid
o Coats calcified cartilage spicules
o Fresh bone then mineralized
- Vascularize Epiphysis
o Postnantal
o Secondary Center of Ossification
o Forms Epihpyseal Plate
- Epiphysiis and Diaphysis Unite

Endochondral Ossification Fetal Finger *Primary Ossification Center (diaphysis)

Bony Collar
- Encircles diaphysis
- Intramembranous Ossification
Calcified Cartilage Spicules (CC)
Note (no secondary center of ossification yet)

Calcification of Cartilage
1. Chondrocytes Hypertrophy and Die
2. Release Alkaline Phosphatase
3. Increase the isoelectric point
4. Calcium Phosphate Precipitates

Endochondral Ossification Zones

Epiphysis

Metaphysis

Diaphysis

Reserve cartilage (resting cartilage)

Blue – calcified cartilage (provides scaffolding for osteoblasts)

Osteoid (on calcified cartilage spicules (need EM to see)

- Osteoprogenitor Cells (on vascular Bud) become Osteoblasts
- Osteoblasts (on calcified cartilage spicules) make osteoid
- Unmineralized osteoid is Mineeral ized (woven bone)
- Osteoblasts trapped in osteoid = osteoCYTES
- Woven bone will be remodeled to become mature bone

Calcified Cartilage Spicule = Blue

Newly formed Mineralized Bone = Red
Mineralization of Osteoid (not just calcification)
- Osteoid (from osteoblast)
o Collagen
o Ground substance
- Mineralization
o Osteoblast matrix vesicles
 Alk Phosphatase
 Pyrophosphatase
 Ca
 PO4
- Hydroxyapatite Crystals - Ca10(PO4)6(OH)

Mineralization Theory
- Osteoblasts make collage + ground substance
- Minteralization Stimulated by:
o Osteonectin- brings in calcium
o Osteocalcin- brings in calcium and hydroxyapetite
o Sialoproteins
- Osteoblasts secrete matrix vesicles
- Hyddroxyapatite Crystals
o Deposit on vesicles
o Rupture vesicles
- Hydroxyapatite fills collagen gap regions
o Confluent = mineralized bone (when collagen gap regions fill with bone and come together)

Calcified Cartilage Spicule

- Layers from Marrow Cavity into Spicule:
1. Osteoblast
2. Unmineralized osteoid (Visible on EM)
3. Mineralized Osteoid (Bone)
4. Calcified Cartilage (Arrows on LM) (def. sign for endochondral ossification – the dark purple inside the
spicule)

Bone Marrow Surrounds Spicule (note Calcified Cartilage)

Long Bone Growth (length vs. width)
- Length
o Epiphyses
o Endochondral
 Epiphyseal plate (Post Natal)
 Due to Secondary Center of Ossivication
 Zones:
o Rest (reserve cartilage)
o Prolifferation (Interstitial growth) – mitosis of chondrocytes
o Hypertrophy of Chondrocytes
o Calcification of Matrix
o Naked Spicules
o Ossification (osteoid deposited)
 Interstitial
o Chondrocytes (model)
o Osteoclasts
 Resorb spicules (remodel)

(growth plate) Zones (1. Rest, 2. Proliferation Proliferation Calcification Begins

3. Hypertrophy, 4. Cacification)

1st Bone is WOVEN BONE

- Collagen random, resembles a woven basket
- More osteocytes than in lamellar adult bone

Pink in between ( woven bone) lighter pink with cells (calcified cartilage spicules)

- Width
o Diaphysis
 o Intramembranous
 Bony Collar
 Appositional
o Osteoblasts (periosteum)
o Osteoclasts
 Resorb at marrow cavity
SUMMARY ENDOCHONDRAL OSSIFICATION
1. Hyaline Cartilage Model
2. Vascularized Perichondrium becomes periosteum (has the osteoprogenators that become osteoblasts)
3. Bony Collar
4. Condrocytes Die (in Diaphysis)
5. Primary Center of Ossification (Periosteal Vascular Bud
6. Osteoprogenitor cells become Osteoblasts
7. Osteoid (Porduced by osteoblasts)
8. Secondary Center of Ossification
9. Epiphysis and Diaphysis Unite

Intramembranous Ossification
- Bones:
o Skull Vault
o Maxilla
o Mandible (most but not all)
o Clavicle (most but not all)

- Within Mesenchyme (membrane)

- Primary bone formation (woven bone)
o Mesenchyme cells differentiate
 Osteoprogenitors  Osteoblasts
 (Osteoid becomes Mineralized Woven Bone)
o Primary Ossification centers (eventually fuse)
o Woven Bone Spicules (Lacunae with Canaliculi but no Lamellae)
o Bone Marrow forms between spicules

(mesenchyme -=-> progenitors  blasts  osteoid Note: mesenchyme Progenitor and blasts line spicules

Osteoid Reviewed
- From osteoblasats
o In endochondral and intramembranous ossification
o Fresh Osteoid (unmineralized)
 Rapidly becomes mineralized
 Norm not visible with LM
 Acidophilic
 Immediately beneath osteoblast
o Mineralized Osteoid
 Less acidophilic (becoming basophilic)
 Toward center of spicule
 Forms woven bone
Endochondral Intramembranous Intramembranous – Fresh Osteoid (blue, EM)
Center = calcified cart. (clear or blue) Center = Bone (dark blue) Mineralizing Osteoid (blue) Center = Bone (red)

Remodeling of Bone
- To release calcium into blood
o Osteoclasts Resorb bone
o Blasts fill the hole with new bonye
o Blasts become cytes
- To change shape of Bone
o Clasts remove
o Blasts place elsewhere
o (response to load changes; Wolff’s Law = bone is modeled to resist forces)

Location of Osteoprogenitor cells (become blasts not clasts – from GM-CFU – monocytes)
- Cancellous bone
o Endosteum (lining of spicules
- Compact Bone
o Endosteum (lines haversian canals)
o Periosteum (osteogenic layer)
Low Serum Ca++
- PTH secreted to increase osteoclast activity (actually blasts stimulated to produce clast activating factor)
- Osteoclasts resorbing bone (multinucleated)
Chronic Renal Failure
- Decreased CA++ and K+
- Increased Fresh Osteoid (slower mineralization)
- Note thick layer of fresh osteoid (red)

LAB HINTS
- Another name for osteon is haversian system
- Decalcified bone and ground bone (calcium still present) are two dif. Histological preps of compact bone which
allow for visulaizaiton of dif. Components of bone. Cementing lines are more easily seen in decalcified –
canaliculi in ground bone. In decalcified bone, collagen fibers remain and are eosinophilic so the bone appears
pink.
- The terms spicules and trabeculae are both used in reference to cancellous bone. Spicules have the appearance
of peninsulas; whereas, trabeculae refer to spicules that anastamose with each other and give cancellous bone a
meshwork appearance.
- During bone dev. Spicules have dif. Appearance depending on if they are undergoing endochondrial or
intramembranous ossification. In contrast, mature spicules have the same appearance, and it is not possible to
know by appearance alone how they originated.
- Epiphysical cartilage and epiphyseal plate both refer to site of endochondral ossification in the epiphysis.
However, when only a primary ossification center exists (diaphysis), the term epiphyseal cartilage is used. When
primary and secondary ossification centers present – plate is used.
- Collagen fibers of both elastic and hyaline cartilage consist of Type II.
- Collagen fibers of fibrocartilage consist of type I collagen as do those of bone.

Sample Questions
1. The specific characteristic that distinguishes a spicule during endochondral ossification from a spicule
undergoing intramembranous ossification is:
a. Calcified cartilage
2. Which one of the following results immediately from the formation of the bony collar during endochondral
ossification?
a. Degeneration and death of chondrocytes
3. Absence of the bony collar would directly affect the dev. Of the? –
a. Diaphysis
4. Failure of a fetal long bone to grow in width could result from lack of healthy?
a. Osteoprogenators in periosteum
5. Death of a new born could result if intramembranous ossification did not propel from the?
a. Skull Vault

Clinical Correlations:
Effect of vitamin and hormonal abnormalities on bone formation

1. Vitamin C deficiency impairs collagen synthesis by osteoblasts, although the osteoid that is produced is
mineralized.
o Results in thin spicules of mineralized bone, as seen in scurvy
2. Vitamin D deficiency causes poor intestinal absorption of calcium and phosphorus, leading to poor
 mineralization of osteoid (soft bone).
o Results in thick spicules of bone containing excessive amounts of eosinophilic, unmineralized osteoid

a. Rickets in children is due to poor mineralization before closure of the epiphyseal plates.
 Clinical features include short stature, flaring of the ribs, bowlegs, knock-knees, craniotabes (soft
skull), and rachitic rosary (nodular swellings where the ribs join the cartilage).
b. Osteomalacia in adults is due to poor mineralization after closure of the epiphyseal plates.
 Clinical features include thickened osteoid seams, bone pain, muscle weakness, and fatigue.
. Excess vitamin A causes premature epiphyseal closure, resulting in short stature.
. Excess growth hormone stimulates liver-derived somatomedin, leading to excessive bone formation.
a. Before epiphyseal closure → pituitary gigantism (elongated long bones)
b. After epiphyseal closure → acromegaly (thickened long bones)
. Deficiency of growth hormone before epiphyseal closure causes pituitary dwarfism.

Broken bones and their repair

1. Initial events after a fracture

a. Thrombus formation
b. Arrival of neutrophils and macrophages, which remove debris
c. Hypoxia of the bone matrix distal to a fracture caused by blood vessel damage
d. Death of osteocytes in osteons
2. Development of a bony callus on the internal and external surfaces at a fracture site
a. Differentiation of osteoprogenitor cells in the endosteum and periosteum into chondroblasts and
chondrocytes
b. The formation of a cartilaginous bridge, or callus, across the break on the periosteal side
(external callus) and endosteal side (internal callus)
c. Endochondral ossification of a callus to produce cancellous bone
3. Remodeling of a bony callus into mature compact bone across the fracture site
a. Forces of stress (weight bearing) cause remodeling of the original architecture.
b. Bone develops the structure that is most suited to resist the forces acting on it (Wolff's law).
MA Study Guide Test 2 – Integument with Mammary Gland

Integ
- Largest organ = 16% b.w.
- 30% of all clinical diagnoses and tumors
- Basal Cell carcinoma – most common malignancy
- Melanoma – most malignant
- Squamous cell carcinoma – less common but more malignant that basal cell

Structure
- Epidermis (cells = keratinocytes – avascular, nutrients and waste through diffusion dermis)
o Stratified, squamous keratinized epithelium
o From ectoderm
o Appendages : ( arise from and continuous with dermis – from ectoderm but extend into dermis)
 Hair follicles
 Nails
 Sweat glands
 Sebaceous glands
 Mammary glands
- Dermis – contains vessels for skin
o Dense, irreg. CT
o From mesoderm
- Hypodermis (superficial fascia)
Layers
- Epidermis
o Stratum corneum (cornified layer)
o Stratum lucidum (clear layer)
o Stratum granulosum (granular layer) – granny cells (keratohyalin granules)
o Stratum spinosum (spinous layer) – thickest layer
o Stratum basale (basal layer, germinativum layer) – single layer – highly proliferative – attach to BM
- Basement membrane (usu. Have a basement membrane b/t epithelial cells and CT)
- Dermis
- Skin separation defect – most likely between dermis and epidermis at the BM

Cell Types in the Epidermis

- Keratinocytes – synthesize intermediate filament keratin
- Melanocytes
o Present in stratum basale
o Derived from neural crest cells
o Produce melanosomes - produce melanin
- Langerhans Cells
o Present in stratum spinosum
o Migrate from bone marrow
o Dendritic cells with immune function – present antigen – phagocytic
o Contain vermiform (Birbeck) granules (histologic feature that makes them very distinctive)
- Merkel Cells
o Stratum basale
o Derived from neural crest cells
o Mechanoreceptors with Merkel cell (neurite complexes)
Cytomorphsis of Keratinocytes

Proliferative Layers
- Stratum basale = basal layer
o Contact basement membrane (basal lamina)
o Hemidesmosomes (between cell and basal lamina)
o Desmosomes – lateral between cells
o Note melanin in keratinocytes
- Stratum spinosum = spinous layer
o Numerous desmosomes
o Contain lamellar/membrane-coating granules – provide lipid protection – water proof
o Express involucrin protein in high concentration- cross link with other proteins to form tough layer
beneath PM.
o Look like they have spines b/t cells = desmosomes (dark spines between cell membranes in EM will see
this again!!!!!!)
- 20-30 days for cells to from basale layer to sloughing corneum
- Malpighian layer (living layer) = basale + spinosum – in theory should see a lot of mitotic figures in these cells –
but mitosis more at night and less during the day when a biopsy would be taken
 - Stratum granulosum = granular layer
o Living cells
o Retain nuclei
o Contain keratohyalin granules
o Release membrane-coating granules (provide surface coating)
o Express filaggrin (fillamintus protein)
o Organelle degradation begins
- Stratum lucidum
o Dead cells – no nucleus
- Stratum corneum
o Dead cells

Dermis

Papillary dermis: numerous cells

- Fibroblast
o Loose collagen
 Type III: reticular fibers
 Type VII; anchoring fibers
o Fine elastic fibers
- Capillaries and arteriovenous anastamoses (shunts) –
o shunt blood to other organ systems – cool skin
- Immune system cells
- Mechanoreceptors
o Free nerve endings
o Meissner corpuscles (shallow)
o Krause corpuscles
Reticular dermis: fewer cells
- Fibroblasts
o Type I collagen
o Thick elastic fibers
- Sweat glands
- Hair follicles
- Arrector pili muscles
- Sebaceous gland
- Mechanoreceptors
o Pacinian corpuscles (Deep)
o Ruffini corpuscles

Thin Skin Vs. Thick Skin

 - Based on epidermal thickness]
- Thick: on palms and soles – lacks hair follicles and assoc. structures (arrector pili and sebaceous glands)

Dermal papillae/ridge

Epidermal rete ridge

vs.

Dermal-Epidermal Junction
- Basement membrane separates epithelium and connective tissue
- Rete apparatus = dermal papillae + epidermal ridges
- Dermatoglyphs (fingerprints) produced by rete apparatus
- Ridges are interdigitations that help anchor dermis to epidermis (note previous illustration – thick skin)

Melanocytes
- melanin is synthesized in melanosomes within melanocytes
o melanin synthesized from tyrosine by tyrosinase enzyme
o tyrosinase enzyme activity is UV-inducible and more active in dark skin
- Cytocrine Secretion of melanosomes containing melanin granules into keratinocytes (very tip of melanocyte is
phagocytosed into keratinocyte)
- Melanocytes are derived from neural crest (important!!!)

Sensory Mechanoreceptors
- Free Nerve endings
o Epidermis and Dermis
- Pacinian corpuscle
o Reticular dermis – pressure, vibration, course touch, tension
- Meissner Corpuscle
o Dermal papillae – light touch
- Krause Corpuscle
o Papillary Dermis – mechanical stimuli
- Ruffini corpuscle
o Reticular Dermis – tensile force

I.d. Pacinian and meissner corpuscle

Pacinian (onin cross section) Meissner (cotton candy) – top of dermal papilli

Epidermal Appendages
- Glands
o Sweat
 Eccrine
 Simple coiled tubular gland
 Duct:
o Stratified Cuboidal
o Opens on surface of epidermis
o Resorbs potassium, sodium and chloride ions
o Excretes urea and lactic acid (toxic products)
 Secretory Unit:
o Mixed: cuboidal, columnar, and pseudostratified columnar
o Merocrine mechanism (small vesicle secreted from cells)
o Dark cells with mucous secretion
o Clear cells with aqueous secretion , intercellular canaliculi, basal striations
 Contractile myoepithelial cells – muscle cells assoc. with glands – smooth muscle like –
myosin and actin help expel secretion from glands with contraction
pics

Secretory portion- have

clear and dark cells –
also can csee
myoepithelial cells lining
(solid pink)

Duct portion (stratified cuboidal

– darker staining

 Apocrine
 Simple of branched coiled tubular gland
 Duct
o Stratified Cuboidal
o Opens into hair follicle
 Secretory unit
o Large lumen stores secretion
o Cuboidal or columnar
o Merocrine mechanism (NOT APOCRIEN)
o Odorless viscous secretion (bact interact causes BO)
o Hormonally responsive – begin function at puberty
o Contractile myoepithela cells (dark boundary on cells)
o Restricted distribution: axilla, anus, areola, auditory canal, eyelids
 o Sebaceous
 Branched tubuloaveolar gland
 Duct
 Stratified squamous
 Usually open into hair follicles
 Secretory unit
 Acini contain small basal cells and large round cells that fill the lumen
 Holocrine mechanism
 Oily sebum secretion
 Hormonally responsive

AP = arector pillae N= nucleous

o Mammary
 Compund tubuloaveloar gland
 15-20 lobes separated by CT (collagen and adipose)
 Each lobe is drained by a lactiferous duct leading to the nipple
 Lactiferous sinus near distal end of duct (storage of secretory product)
 Duct near nipple is stratified squamous then cuboidal then columnar
 Identical in male/female until puberty
 Estrogen and progesterone (ovary)
 Prolactin (anterior pituitary) – stimulates milk production (pro lactin = pro duction)

 Inactive gland – similar to lactating but alveoli are not developed

 Lactating Mammary Gland
 Develops due to elevated progesterone and estrogen
 Ducts grow and branch
 Alveoli develop and mature
o Cuboidal cells
o Myoepithelial cells
 Colostrum accumulates
o Eject day 1-3 after birth
o Contains lymphocytes, monocytes, antibodies, lactalbumin, minerals,
electrolytes (whole cells)
o Oxytocin (posterior pituitary) – stimulates milk ejection
o Be able to disting Alveolus from duct in both inactive and lactating mammary
gland
 Al = alveolus (lactating) Duct
CT = connective tissue

- Hair follicles
o Growth occurs by proliferation of keratinocytes in matrix of hair bulb
 Growth phases: Anagen, Catagen, Telogen
 Controlled by dermal papillae (contain capillaries that stim. Hair growth if they regress the hair
will stop growing)
 Hormonally responsive
o Melanocytes in matrix determine hair color (can see brownish at junction of dermal papilla and matrix
o Arrector pili muscle connects to papillary dermis
o Layers (outside to in)
 Connective tissue sheat
 Basal lamina
 External root sheath (living layer of keratinocytes)
 Internal root sheath (living layer of keratinocytes)
 Hair (cuticle, cortex, medulla)

(HR – hair root (matrix) P- dermal papillae) (C = cuticle, E = external root sheath, I = internal root
sheath)

(hair follicles and ducts of glands are important sources of regenerative keratinocytes in cutaneous wound healing)
 - Nails
o Nail plate lies in nail fold
 Eponychium at proximal fold forms nail cuticle
 Lateral nail fold forms nail grooves
o Nail bed (matrix- proliferating keratinocytes) underlies nail plate
 Nail root is in proximal nail fold
 Growth occurs in the matrix
 Matrix is visible through nail as lunula (white region)
 Hyponychium – lies under distal end of nail plate

Eponychium

Nail Bed

NB – Nail Bed
Hy – hyponychium
Nail matrix Nail Plate
D – Dermis

Clinical Correlations:

Ultraviolet light darkens the melanin and speeds tyrosinase synthesis, thus
increasing melanin production. Also, pituitary ACTH influences
pigmentation. In Addison's disease there is insufficient production of
cortisol by the adrenal cortex so excess ACTH is produced, which leads to
hyperpigmentation.

Albinism is the absence of melanin production resulting from a genetic

defect in tyrosinase synthesis. Melanosomes are present but the melanocytes
fail to produce tyrosinase.

Ultraviolet rays exist as two types. Ultraviolet B(UVB) is the component in sunlight that produces sunburn, whereas
ultraviolet A(UVA) is responsible for tanning. Until recently, it was believed that UVA was relatively safe but it appears
that UVA radiation penetrates the skin and damages the deep layers, producing mutations that are implicated in tumor
progression.

Psoriasis is a disease characterized by patchy lesions caused by greater keratinocyte proliferation in the stratum
basale and stratum spinosum and an accelerated cell cycle (turnover is increased as much as seven times),
resulting in accumulations of keratinocytes and stratum corneum. The lesions are common on the scalp, elbows,
and knees, but they may occur almost anywhere on the body. In some cases, the nails may also be involved.
Psoriasis is an incurable but manageable chronic condition whose symptoms periodically escalate and then
diminish with no apparent cause.

Warts are benign epidermal growths caused by infection of the keratinocytes with papillomaviruses. The
resulting epidermal hyperplasia thickens the epidermis with scaling. Deeper ingrowth of the dermis brings
capillaries closer to the surface. Warts are common in children, young adults, and immunosuppressed patients.

Basal cell carcinoma, the most common human malignancy, arises in the stratum basale cells of the
epidermis and usually is caused by exposure to ultraviolet radiation. Although basal cell carcinomas do not
usually metastasize, they are destructive to local tissue. Of the several types of lesions that occur, the most
common is the nodular variety, characterized by a papule or nodule with a central depressed "crater" that
eventually ulcerates and crusts. These lesions are most common on the face, especially the nose. Surgery is
the usual treatment, and up to 90% of patients recover with no additional sequelae.

Squamous cell carcinoma, slow growing the second most common skin cancer, arises in the
keratinocytes of the epidermis. It is locally invasive and may metastasize. It is characterized
by a hyperkeratotic scaly plaque or nodule that often bleeds or ulcerates. It invades deeply,
resulting in fixation to the underlying tissues. Several factors may cause this disease,
including ultraviolet radiation, x-irradiation, soot, chemical carcinogens, and arsenic. The
lesions are most common on the head and neck. Surgery is the usual treatment of choice.

Malignant melanoma, a skin cancer, is most prevalent in fair-skinned individuals and is increasing in
incidence. It is usually associated with excessive exposure to the sun. Malignant melanoma is very
invasive because the malignant cells originate from transformed melanocytes; the melanocytes penetrate
the dermis and enter lymphatic vessels as well as the bloodstream to gain wide distribution throughout the
body.

Acne, the most common disease seen by dermatologists, is a chronic inflammatory disease involving the sebaceous
glands and hair follicles. Obstructions resulting from impaction of sebum and keratinous debris within hair follicles is one
cause of acne lesions. Anaerobic bacteria near these obstructions may contribute to development of acne, although the
role of bacteria is not clear. However, the efficacy of antibiotic treatment for acne supports the idea of bacterial
involvement in its pathogenesis. The disease is most severe in boys, with onset commonly from age 9 to 11 years, when
increasing levels of sex hormones begin to stimulate the sebaceous glands. Acne usually subsides through the later teen
years, but it may not resolve until the fourth decade of life. In some people, acne does not begin until adulthood.

Mothers who cannot breast-feed their infants on a regular feeding schedule are inclined to suffer from poor
lactation. This may motivate a decision to discontinue nursing altogether, with the result that the infant is
deprived of the passive immunity conferred by ingesting antibodies from the mother.

Breast cancer, second only to lung cancer as one of the major causes of cancer-related death in women,
may be of two different types: ductal carcinoma of the ductal cells and lobular carcinoma of the terminal
ductules. Detection must be early, or the prognosis is poor because the carcinoma may metastasize to the
axillary lymph nodes and from there to the lungs, bone, and brain. At the recommendation of the medical
profession, early detection through self-examination and mammography has helped to reduce breast cancer
mortality rates.

Nail Defects –
Abnormal nails are associated with some diseases.
- Nails should appear pinkish due to the blood vessels in the underlying dermis.

a. A pale or bluish nail bed may indicate cardiovascular problems or poor oxygenation of the circulating
blood (cyanosis).
b. Split nails are associated with nutritional deficiencies.
c. Clubbing (thickening) at the nail base may indicate lung cancer.
d. Spoon-shaped nails (koilonychia) are associated with iron deficiency anemia.

Keloids - abnormal scar tissue that is elevated, firm, and rounded, with irregular margins

 These lesions result from abnormal wound healing or skin injury involving excessive formation of type
III collagen in the dermis.

Elastosis - loss of skin elasticity (wrinkles) accompanied by an increase in stainable elastin in the dermis

 This condition commonly occurs with aging and can result from excessive exposure to sunlight.

Seborrhea - any of several skin diseases marked by very oily skin resulting from overproduction of sebum

Keratosis

 Ichthyosis vulgaris: the most common inherited disorder (autosomal dominant) of keratinization, with onset
in childhood

 Dry scales are present on the trunk and extremities; histologic features include hyperkeratosis and
absence of the stratum granulosum.

Seborrheic keratosis: a benign skin tumor arising from basal cells and usually occurring in middle age. Lesions often
develop rapidly in crops, presenting as yellow or brown raised soft plaques. A rapid increase in size and number of these
lesions, known as Leser-Trélat sign, may indicate internal malignancy, especially of the gastrointestinal tract.

Actinic (solar) keratosis is a precursor lesion for squamous cell skin cancer. Tumor cells resemble prickle cells of the
stratum spinosum and are characterized by "keratin pearls." Skin lesions commonly are firm, red, painless small bumps,
which initially are localized and superficial but may later invade and metastasize.

Pemphigoid diseases

Bullous pemphigoid is an autoimmune disease characterized by chronic blisters (bullae) in the skin, mainly on the thighs,
arms, and abdomen. It is associated with immunoglobulin G autoantibodies against hemidesmosomes and usually is
seen in the elderly.

Kaposi’s sarcoma

Clinically, Kaposi's sarcoma is characterized by bluish-red cutaneous nodules, usually first appearing on the
legs, toes, or feet, that slowly enlarge and spread to more proximal sites.

o In patients with AIDS, Kaposi's sarcoma is associated with herpes infection (HHV8).
o Histologically, the lesions exhibit vascular proliferation with slitlike channels composed of
malignant spindle-shaped cells, probably of endothelial origin.

LAB:
 - In the normal condition, the papillary layer of the dermis contains more cells of the immune system and more
capillaries than do the reticular layer of the dermis and the epidermis. Defense cells are part of the integument,
which functions in protection. These cells are strategically located in the papillary layer of the dermis, which is
composed of loose connective tissue so cells can easily migrate and monitor the epidermis from below. Immune
cells are ready to attack any foreing invaders that make it through the epidermis such as in a wound situation.
Capillaries in the papillary layer of the dermis provide a means for nutritive products to diffuse to the near-by,
avascualr epidermis and for dissipation of body heat.
- Although melanocytes make melanin, they transport it immediately to keratinocytes. Therefore, melanin is
visible in keratinocytes not in melanocytes.
- Stratum lucidum, present in thick skin, is not usually visible in photomicrographs of section of the epidermis but
can be seen in textbook illustrations.

Sample Questions:

1. When stained immunohistochemically, a malignant fibrous histiocytoma of the connective tissue is found to be
positive for keratin. Transmission EM is ordered to confirm the presence of keratin in this tumor of mesodermal
origin. Which of the following structures would be seen in or around the tumor cells?
a. Tonofilaments (?)Numerous bundles and single (10-nm) intermediate filaments (tonofilaments) course
through the plaques of the laterally placed desmosomes and end in plaques of hemidesmosomes.
2. A patient with a deep cutaneous wound over the anterior tibia comes to your office because the wound has
failed to heal. You explain that normal wound healing proceeds with proliferation of _________ that
resynthesize the extracellular collagen matrix of the dermis. Remodeling of the collagen fibers causes shrinkage
of the wound margin and ultimate closure of the wound. Epithelial proliferation and migration across the newly
formed dermis progresses to provide the barrier function of the skin.
a. A Fibroblasts (? Why not keratinocytes?)
3. Histologic defects in desmosomes due to autoimmune reaction against desmoglein is characteristic of
pemphigus vulgaris disease. The primary consequence of this dysfunction is?
a. Dyhesion between keratinocytes
4. During pregnancy, estrogen and progesterone induce growth of mammary glands and production of colostrums.
Estrogen and progesterone levels decline a few days after birth. At that time, whih of the following hormones
stimulates production and secretion of milk from the lactating breast?
a. Prolactin and oxytocin