Rate of Growth

Varies at different age: maximal growth rate: fetus highest postnatal growth: just after birth slower rate in mid-childhood increased growth rate during puberty / pubertal growth spurt girls 8-13 boys 9-14 years dependent especially on GH and gonadal steroids after puberty, the epiphyses of long bones fuse --> growth ceases --> maximal height achieved

Growth and Development

Is genetically determined Its full potential depends on: Nutrition Health (illness and stress inhibit growth) Hormones Growth Hormone (GH) Somatomedins / Insulin-like Growth Factors: IGF-I, IGF-II Thyroid hormones: Tri-iodothyronine (T3) Tetra-iodothyronine (T4) / Thyroxine Gonadal Steroids (sex hormones) Parathormone 1,25-dihydrocholecalciferol (1,25 DHC / calcitriol) Calcitonin

Bone

Fungsi utama tulang

1. Fungsi ekstrimitas dan pelindung alat vital 2. Tempat melekat otot rangka 3. Menjadi tempat ion penting bagi tubuh seperti Ca,P,Mg,S yang sangat penting untuk kehidupan dan dapat digunakan tubuh saat tdk ada/kurang ion pd tubuh 4. Rumah bagi elemen hematopoetik

Bone

Compact bone Outer layer of bone, surrounding trabecular bone & bone marrow cavity Much denser, less active metabolically Compose 75% of bone in the body Nutrients are provided via Haversian canals blood vessels Collagen arrangement around Haversian canals osteon cylinders (Haversian system) Trabecular bone Spongy bone: bone spicules separated by spaces Compose 25% of bone in the body Nutrients diffuse from bone ECF

Bone

Organic matrix 30% content of compact bone Collagen fibers: 90-95% Fibers extend primarily along the lines of tensional force; give the powerful tensile strength Homogeneous gelatinous medium ground substance: 5-10% Extracellular fluids + proteoglycans (chondroitin sulfate & hyaluronic acid) Help control the deposition of calcium salts
Bone salts 70% content of compact bone Crystalline salts (principally calcium & phosphate): hydroxyapatite, Ca/P ratio: 1.3-2.0; long, flat shaped crystal plates; compressional strength Mg, Na, K, carbonate Bone cells Osteoblasts Osteocytes Osteoclasts

Bone cells
Osteoblasts Bone forming cells Derived from bone marrow cell precursors Secrete large quantities of type I collagen + other matrix proteins Secrete growth factors IGF-1, secrete cytokines IL-1, IL-6 Receptors for PTH, DHC, estrogens Differentiate into osteocytes Osteocytes Rounded cells surrounded by bone matrix Send long processes: into the canaliculi, contact and form tight junctions with processes of other osteocytes, ramify throughout the bone function in Ca++ exchange with the ECF

Figure 21 2.
Structure of compact and trabecular bone. The compact bone is shown in horizontal section (top) and vertical section (left). (Reproduced, with permission, from Williams PL et al (editors): Gray's Anatomy, 37th edition, Churchill Livingstone, 1989.)

Bone cells

Osteoclasts

Derived from hematopoietic stem cells through monocytes

Erode and resorb previously formed bone: proton pump acidify the matrix ( pH 4) dissolves hiydroxyapatite calcium and phosphate ion acid proteases dissolve collagen amino acids shallow depression in the bone bone-resorbing compartment

OSTEOBLASTOGENESIS - OSTEOCLASTOGENESIS
Bone Marrow Culture Fibroblast ColonyForming Unit (Osteoprogenitor cells) Osteoblast, Fibroblast Chondrocytes, Adipocytes Progenitors PTH Calcitriol RANK-L Granulocyte-Macrophag Colony Forming Unit (Hematopoetic cells) Osteoclast, Monocytes Macrophage Progenitors

(-)

Osteoblastic precursor cells

Estrogen Androgen

Early pre-osteoclast
(+) Late pre-osteoclast

(+) (+) Osteoblast IGF-1 Bone Forming

(+) Osteoclast Bone Resorption

(RANK: receptor activator of nuclear factor kappa B) = (ODF: osteoclast differentiation factor)

Osteoblast Osteoclast Communication

osteoblast (& osteoblast precursors) estrogens glucocorticoids PTH osteoprotegerin (OPG) free-floating decoy receptor + + estrogens

OPG-ligand (RANK ligand)

osteoclast precursors RANK receptor +

osteoclast + RANK receptor

osteoclast activity

RANK ligand (osteoblast) +

bone resorption PTH, DHC (vit D3), IL 1- 4 - 6-11-17, TNF-alfa

Osteoblast Produces bone matrix Mediating osteoclast activity parathormone (PTH) osteobalstic + osteoprotegerin (OPG) ligand precursor osteoblast bone formation cells + + soluble mediators + osteoclast bone resorption activity

release matrix growth factors (transforming growth factor- / TGF- )

Bone Formation & Resorption

Bone is constantly being resorbed and formed Modelling Processes involved in formation of the skeleton Most active during childhood and adolescence Ceases at maturity (age 18-20 yrs) Long bones increase in diameter, change shape and develop a marrow cavity related to stresses and strains imposed on skeleton by gravity and other factors Bone strength adjustment to heavy loads /mechanical forces changes in bone shapes and thickness bone rearrangement for proper support

Bone Formation & Resorption

Bone is constantly being resorbed and formed Remodelling Processes occurring at bone surfaces before and after adult development to maintain the structural integrity of the bone that continues throughout adult life No net gain or loss of skeletal mass after longitudinal growth has ceased. Bone resorption equally balanced by bone formation in a healthy skeleton Local process: bone-remodeling units osteoclasts resorb bone, osteoblasts form new bone 100 day cycle (3-4 months; 3 weeks resorption by osteoclasts, deposition afterwards by osteoblasts) 5% of bone mass is remodeled at any one time by + 2 million boneremodeling units; 4%/year for compact bone, 20%/year for trabecular bone

Bone Formation & Resorption

Equilibrium Between Bone Deposition and Absorption

In growing bones, the rate of bone deposition exceeds that of bone

absorption

The epiphyses of long bones fuse growth ceases

maximal height achieved (20-21 yrs) peak bone mass age (35 yrs): the rate of bone deposition and bone absorption are equal / constant total bone mass / plateau deposition osteopenia osteoporosis

After 35 yrs: the rate of bone absorption exceeds that of bone

Bone Formation & Resorption

Repair of a fracture Maximal activation of all periosteal and intraosseous osteoblasts at the fracture site Immediate formation of immense number of osteoblasts development of large bulge of new organic matrix followed by calcium salts deposition callus formation; then reshaped into appropriate structure within months

Bone Growth
During growth
Epiphyseal plate

Plate of actively proliferating cartilage Separates epiphyses of long bones from its shaft Lays down new bone on the end of the shaft, finely balanced cycle of
cartilage growth, matrix formation and calcification of cartilage

Its width is proportionate to the rate of growth, affected by hormones,

most markedly by GH and IGF-1

Linear bone growth ceases after the epiphyses unite with the shaft of
the bone (epiphysial closure): > Cartilage cells stop proliferating, hypertrophic vascularization, ossification. > Epiphysial closure of bones is an orderly temporal sequence bone age can be determined by x ray

Structure of a typical long bone before (left) and after (right) epiphysial closure

Bone Growth

Fetal development Enchondral bone formation Most of the bones Modeled in cartilage transformed into bone / ossification Intramembranous bone formation Clavicles, mandibles, bones of the skull Mesenchymal cells form bones

The Hormones

Control of Growth Hormone Secretion

Brain stress centers Brain sleep centers chemical stimuli sex steroids Hypothalamus GIH GRH (Somatostatin) Somatotroph cells of anterior pituitary GH Liver (and other organs) Somatomedins (IGF-I, IGF-II) Tissues Growth and cellular differentiation in bone, muscle and adipose tissue activates inhibits

Growth Hormone and IGF-I Actions

Growth hormone

Na+ decreased retention insulin sensitivity

lipolysis

protein synthesis

epiphysial growth

IGF-I

insulin-like activity

antilipolytic activity

protein synthesis

epiphysial growth

Growth Promoting Actions of GH on Soft Tissues Mediated by Somatomedins

Increasing the number of cells (hyperplasia) Stimulating cell division Preventing apoptosis (programmed cell death) Increasing the size of cells (hypertrophy) Favoring protein synthesis (main structural component of cell) Stimulates aspects of protein synthesis Promotes amino acids uptake by cells Promotes DNA transcription Promotes RNA translation Inhibits protein degradation

Somatomedins Insulin-like growth factor-1 (IGF-I) and Insulin-like growth factor-2 (IGF-II)

Polypeptide growth factors, interacts with GH

Synthesized in and secreted by the liver, osteoblasts & cartilage (chondrocytes) and other tissues in response to GH stimulation

In human bone matrix IGF-II is present in 10-15-fold greater concentrations than IGF-I
Stimulate osteoblast and chondrocyte proliferation, induce differentiation in osteoblasts and maintain the chondrocyte phenotype

Somatomedins

Promotes skeletal and extra skeletal growth Insulin-like effects Increased glucose uptake Increased amino acids uptake Increased protein synthesis Glucocorticoids reduce IGF activity High levels of estrogens inhibits IGF production

Effects of Thyroid Hormones on Growth and Development

Promote normal growth

Stimulate GH production and secretion Enhance GH effects Promote IGF-I production by the liver

Promote development and maturation of

Nervous system promote nerve growth factor (NGF) Promote neural branching (synapses) Promote myelinization of nerve fibers

Essential for normal cell division, differentiation, and

maturation in the developing fetus, especially in the brain and skeleton

The human parathyroid glands, viewed from behind.

Kelenjar paratiroid

Section of human parathyroid. (Reduced 50% from x 960.) Small cells are chief cells; large stippled cells (especially prominent in the lower left of picture) are oxyphil cells. (Reproduced, with permission, from Fawcett DW: Bloom and Fawcett, A Textbook of Histology, 11th ed. Saunders, 1986.)

Parathyroid hormone. The symbols above and below the human structure show where amino acid residues are different in bovine and porcine PTH. (Reproduced, with permission, from Keutmann HT et al: Complete amino acid sequence of human parathyroid hormone. Biochemistry 1978;17:5723. Copyright 1978 by the American Chemical Society.)

Signal transduction pathways activated by PTH or PTHrP binding to the hPTH/hPTHrP receptor. Intracellular cAMP is increased via Gs and adenylyl cyclase (AC). Diacylglycerol and IP3 (1,4,5-InsP3) are increased via Gq and phospholipase C (PLC). (Modified and reproduced, with permission, from McPhee SJ, Lingappa VR, Ganong WF [editors]: Pathophysiology of Disease, 4th ed. McGraw-Hill, 2003.)

Parafollicular cells in the thyroid. (Modified from Poirier J, Dumas JLR: Review of Medical Histology. Saunders, 1977.)

Human calcitonin.

Calcium

Fungsi Kalsium

Pembentukan mineral tulang Pertumbuhan dan pemeliharaan tulang Garam hidroksiapatit (hydroxyapatite): Ca10(PO4)6(OH)2

Pembekuan darah
Kontraksi otot Second messenger: IP3 End. Ret ion Ca enzim Penglepasan hormon dan neurotransmiter Fungsi saraf

Ca++ vital roles

1. Neuromuscular excitability Ca++ Em muscular excitability Ca++ Em muscular excitability cardiac arrhythmia Excitation-contraction coupling in cardiac & smooth muscle Ca++ myocardial, and smooth muscle contractility (particularly)

2.

3.

Stimulus-secretion coupling Ca++ entry into secreting cells (endocrine cells, nerve cells) in response to stimulation secretory product (peptide hormones, catecholamines, neurotransmitters) exocytosis Blood clotting

4.

Pengendalian Homeostasis Kalsium

Pengendalian absorpsi Ca di usus (vit D3) Pengendalian reabsorpsi Ca di ginjal

PTH : reabsorpsi 1,25 DHC : reabsorpsi Kalsitonin : reabsorpsi

Pengendalian kalsium tulang

PTH & Kalsitonin

Calcium Distribution
Total Calcium 1100 g 1.5% BW Bone Calcium 99% total Plasma Calcium 1% total 10 mg/dL-2.5 mmol/l

Diffusible 1.34 mmol/l 59% plasma calcium

Nondiffusible 1.16 mmol/l 41% plasma calcium (protein-bound)

Ionized (Ca++) 1.18 mmol/l 50% plasma calcium

Complexed to HCO3, citrate 0.16 mmol/l 9% plasma calcium Bound to albumin 0.92 mmol/l Bound to globulin 0.24 mmol/l

Relation between plasma Ca2+ concentration and PTH response in humans. The set point is the plasma Ca2+ at which half the maximal response occurred. (Modified and reproduced, with permission, from Brown E: Extracellular Ca2+ sensing, regulation of parathyroid cell functions, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 1991;71:371.)

Formation and hydroxylation of vitamin D3. 25-Hydroxylation takes place in the liver, and the other hydroxylations occur primarily in the kidneys. The formulas of 7dehydrocholesterol, vitamin D3, and 1,25-dihydroxycholecalciferol are also shown.

Parathormone and 1.25 (OH)2Cholecalciferol

7-dehydrocholesterol cholecalciferol (vit D3) 25(OH)D3 Prolactin PTH

24.25(OH)2D3

1.25(OH)2 D3

Intestine Ca++ absorption Bone resorption Kidney Ca++ Kidney PO4 ion reabsorbtion reabsorption

plasma Ca++

plasma PO4 ion

Calcitonin

Control of secretion
Secreted by the parafollicular cells
[Ca++] > 9.5 mg/dl calcitonin Estrogen calcitonin Glucagon calcitonin

Calcitonin
Effects Kidneys Calcitonin membrane receptors on renal tubules cells Calcium reabsorption Phosphate reabosrption Bones Calcitonin membrane receptors on osteoclast osteoclast activity bone resorption Ca and PO4 release Blood [Ca++] [PO4]

Calcitonin
Prevents bone resorption excess in pregnancy

estrogen
+ calcitonin

prolactin
1.25 DHC

bone resorption [Ca ++] + faster -- inhibit

 . Estrogens inhibit secretion of cytokines such as IL-1, IL-6, and TNF, and these cytokines foster the development of osteoclasts. Estrogen also stimulates production of TGF-, and this cytokine increases apoptosis of osteoclasts. However, it now appears that even small doses of estrogens may increase the incidence of uterine and breast cancer

Total body calcium, an index of bone mass, at various ages in men and women. Note the rapid increase to young adult levels (phase I) followed by the steady loss of bone with advancing age in both sexes (phase III) and the superimposed rapid loss in women after menopause (phase II). (Reproduced, by permission of Oxford University Press, from Riggs BL, Melton LJ III: Involutional osteoporosis. In Evans TG, Williams TF (editors): Oxford Textbook of Geriatric Medicine. Oxford Univ Press, London, 1992.)

Cortisol

Antigrowth effects
Promoting protein breakdown Blocking the secretion of GH Inhibiting growth in long bones

Normal trabecular bone (left) compared with trabecular bone from a patient with

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