Current perspectives in residual ridge remodeling and its clinical implications: A review

Leila Jahangiri, BDS, MMSc,a Hugh Devlin, BDS, PhD,b Kang Ting, DMD, DMSc,c and Ichiro Nishimura, DDS, DMSc, DMDd Harvard School of Dental Medicine, Boston, Mass.; University Dental Hospital of Manchester, Manchester, United Kingdom; and UCLA School of Dentistry, Los Angeles, Calif. Purpose. This article reviews the current understanding of the biology of tooth extraction wound healing and residual ridge remodeling. Methods. The review of the biology of tooth extraction wound healing involves a discussion of the different cells populating the tooth extraction wound, the matrix formation, and the control of the repair process in the short-term. Defects in socket matrix formation or cellular activity will lead to stalled healing. The review of residual ridge remodeling describes the long-term result of tooth extraction and formation of residual ridges, in which the quantity of bone tissue continuously decreases. This may suggest that any potential regulatory factors of residual ridge resorption should have an adverse effect either on the increased catabolic activity by osteoclasts or on the decreased anabolic activity by osteoblasts. Both short-term tooth extraction healing and long-term residual ridge remodeling processes are interdependent. Furthermore, any potential genetic and environmental regulatory factors can affect the quality and quantity of bone by altering the gene expression events taking place in bone cells. Results. The intent of this article was to review the current progress of biologic research on residual ridge remodeling and to relate the changes at molecular, cellular, and tissue levels. The understanding of residual ridge remodeling may provide a sound scientific basis for improved restorative and therapeutic treatments of the edentulous population. (J Prosthet Dent 1998;80:224-37.)

CLINICAL IMPLICATIONS
This review addressed the cellular and extracellular matrix component of alveolar bone regeneration. The cellular component is sensitively responding to the mechanical and biologic environments such as removable partial denture and osteoporosis. Uncovering these regulatory mechanisms may lead to a new therapeutic modality in maintaining and further regeneration of the residual ridge alveolar bone. The heterogeneous reaction by osteoblasts to a newly characterized extracellular matrix containing type II and type IX collagens has provided a puzzling but exciting result, which seems to postulate two independent remodeling processes that regulate cortical bone and trabecular bone separately. The proposed distinct remodeling processes may be directly applied to osseointegration phenomenon in which cortical and trabecular bones may provide different consequences.

Presented in part before the Academy of Prosthodontics, Tucson, Arizona, May 1995. This review was partly based on investigations supported by Procter & Gamble Fellowship Award (L. Jahangiri), British Diabetic Association (H. Devlin), and NIH grants, EY08219, and DE10870 (I. Nishimura). aInstructor of Restorative Dentistry (Prosthodontics), Harvard School of Dental Medicine. bSenior Lecturer in Restorative Dentistry, University Dental Hospital of Manchester, University of Manchester. cAssistant Professor of Orthodontics, UCLA School of Dentistry. dAssociate Professor Section of Advanced Prosthodontics, UCLA School of Dentistry and Director, Center for Reconstructive Biotechnology. 224 THE JOURNAL OF PROSTHETIC DENTISTRY

esidual ridge is a term used to describe the shape of the clinical alveolar ridge after healing of bone and soft tissues after tooth extractions. After tooth extraction, a cascade of inflammatory reactions is immediately activated, and the extraction socket is temporarily closed by the blood clotting. Epithelial tissue begins its proliferation and migration within the first week and the disrupted tissue integrity is quickly restored. Histologic evidence of active bone formation in the bottom of the socket is seen as early as 2 weeks after the extraction and the socket is progressively filled with newly formed bone in about 6 months.1,2 The most striking feature of the extraction wound healing is that even
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Fig. 1. Longitudinal observations by standardized lateral cephalographs on continuous resorption of maxillary and mandibular residual ridge before tooth extraction (A), and 3 months (B), 7 months (C), 17 years (D), and 25 years (E) after extraction. Superimposed cephalographs depict that large amount of bone structure was removed during this time (F).

after the healing of wounds, the residual ridge alveolar bone undergoes a life-long catabolic remodeling. The size of the residual ridge is reduced most rapidly in the first 6 months, but the bone resorption activity of residual ridge continues throughout life at a slower rate, resulting in removal of a large amount of jaw structure (Fig. 1).3-10 This unique phenomenon has been described as residual ridge reduction (RRR) (Table I).11 The rate of RRR is different among persons, and even at different sites in the same person. Residual ridge remodeling directly affects the function of removable prostheses, which rely greatly on the quantity and architecture of the jaw bones.12-17 The RRR phenomenon is easily observed clinically after tooth extraction, but the sequence of biologic events is not well-understood. Since the first reports of substantial resorption of the edentulous residual ridge by
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Table I. Clinical features of reduction of residual ridges (RRR)

Definition Continuous size reduction of the residual ridge, largely due to bone loss after tooth extraction. General feature RRR is chronic, progressive and irreversible. The rate is fastest in the first 6 months after extraction. Rate is variable between different persons within the same person at different times within the same person at different sites Has a multifactorial cause anatomic factor prosthetic factor metabolic and systemic factor functional factor

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Table II. Etiologic factors of reduction of residual ridges (RRR)

Etiologic factor Correlation with RRR Source

Anatomic factor Mandible

Short and square face Large alveolar process Density of alveolar bone Labial alveoloplasty

4 more RRR than maxilla Inconclusive Increased RRR Direct effect of masticatory force? Increased RRR No correlation with the jaw size Classification postulated No correlation with bone density Increased RRR No correlation

Tallgren23 Atwood and Coy31 Tallgren23 Mercier and Lafontant113 Wictorin25 Atwood and Coy31 Wilson114 Atwood and Coy31 Gazabatt et al.40 Michael and Barsoum45 Wictorin25 Wictorin25 Johnson42,43 Carlsson et al.26-28 Winter et al.32 Woelfel et al.33 Wictorin25 Carlsson26-28 Atwood and Coy31 Winter et al.32 Atwood and Coy31 Mercier and Inoue75 Kribbs et al.76 Ortman et al.115 von Wowern and Kellerup37 Nishimura et al.35 Nishimura et al.79 Wical and Brussee36 Mesrobian and Shklar116 Olson and Hagen117 Fenton and El-Kassem118 Nishimura et al.63 Campbell38 Carlsson41 Carlsson et al.26-28 Carlsson et al.29 Kelly47 Tallgren24 Nicol et al.119 Bergman and Carlsson120 Atwood and Coy31 van der Kuij et al.121 Ortman et al.122

Prosthodontic factor Immediate denture

Decreased RRR No correlation Increased RRR

Zero degree teeth

Metabolic and systemic factor Age and sex

No correlation with the rate of RRR

Osteoporosis

No correlation with the ridge height

Ca and Vit D supplement Zinc sulfate supplement Dichloromethane diphosphonate supplement Sodium fluoride supplement Indomethacin supplement Functional factor Intensive denture wearing

Smaller maxillary ridge Knife-edge type mandible Knife-edge type in monkeys Decreased RRR Better ext. healing in hamsters Decreased RRR in rats No correlation (but better calcification) Decreased RRR in rats Increased RRR

Regular denture wearing

Combination syndrome No correlation with the rate of RRR

(Statistically insignificant trend)

Other factor Bioelectric potential

Decreased RRR by exogenous pulsed electromagnetic fields in dogs

Thompson,18 Atwood,19 and Tallgren,20 a number of studies have been conducted to describe the structure of the changing residual ridge using standardized measurements of lateral cephalographs,21-35 panoramic radiographs,36,37 or diagnostic casts.38-45 In 1979, Atwood46 postulated that there are four major etiologic
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factors that cause RRR: anatomic, prosthetic, metabolic, and functional factors. The primary goal of those descriptive studies was therefore to elucidate a pathologic cause of the severe form of RRR. These observations in edentulous patients are not conclusive and, to date, no single factor alone has been found to contribute to
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Fig. 2. Panoramic radiograph (A) and intraoral photograph (B) of patients exhibiting severe localized bone resorption at anterior segment of maxillary residual ridge. Hypothetical scheme (C) has been postulated that mechanical stress may induce local synthesis of messenger signals such as prostaglandins, which then activate osteoclastic bone resorption (OC) at surface of residual ridge alveolar bone. Bar = 200 m.

the severe form of RRR (Table II). However, there are several consistent observations that suggest that local mechanical stress often generated by removable prostheses may affect the state of residual ridges. Other studies pointed out that postmenopausal osteoporosis has attracted much attention in causal relation to RRR. The first objective of this article was to review local mechanical stress and systemic osteoporosis as potential factors that influence the long-term sequelae of tooth extraction and resorption of residual ridges, in which bone tissue is adversely affected, either on the increased catabolic activity by osteoclasts or on the decreased anabolic activity by osteoblasts. The second objective was to review the current understanding of the biology of extraction wound healing, which involves a discussion of the different cells populating the extraction site, matrix formation, and short-term control of the repair process. The residual ridge is primarily composed of unique oral soft tissue and alveolar bone, both of which are formed as a result of tooth extraction wound healing. Defects in socket matrix formation or cellular activity will lead to stalled healing, and any potential genetic and environmental regulatory factors can affect the quality and quantity of bone by altering the gene expression events. Therefore this article reviewed current progress of biologic research on residual ridge remodeling, relating the changes at molecular, cellular, and tissue levels.
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In this article, all efforts were made to comprehensively list the dental literature that is thought to be relevant to RRR. The results from most of these studies are summarized in Table II; however, it was not our intent to verify the data and conclusions of all these studies. Thus, although in-depth analyses are provided for the biologic data on tooth extraction socket healing and long-term residual ridge remodeling from selected articles, the list in Table II should serve only as an index for RRR studies.

LOCAL AND SYSTEMIC FACTORS INFLUENCING THE RESIDUAL RIDGE REMODELING Mechanical stress by prosthesis affecting bone resorption
It is observed that patients with combination syndrome, as described by Kelly,47 exhibit severe RRR in the anterior segment of maxillary residual ridge (Fig. 2). An exaggerated mechanical stress applied to the maxillary complete denture from the remaining mandibular anterior teeth has been postulated to cause this site specific RRR. It was suspected that excessive mechanical stresses were responsible for the less advantageous residual ridges observed in the institutionalized patients who wore their complete dentures for long hours than the edentulous ridges of the patients in the same institution who refused to wear their dentures.38
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A prospective clinical study addressing the mechanical factors on RRR was conducted by Carlsson et al.4,29 in which partially edentulous patients (Kennedy class I) were divided into three experimental groups wearing (1) no mandibular denture, (2) partial denture with bilateral free-end denture bases, and (3) partial denture with anterior alveolar bar. The longitudinal observation of the edentulous ridge of these patients revealed the increased rate of RRR in the groups of wearing dentures. Bone that receives constant mechanical stimuli maintain a coupled cellular activity between osteoclasts and osteoblasts. When the bone tissue is placed in a state of immobilization or a weightless environment, it bears less mechanical stress and cannot sustain the normal coupled remodeling process and results in loss of calcified bone mass described as disuse atrophy.48,49 Conversely, applied mechanical force can stimulate bone apposition. For example, facial bone remodeling in mountain gorillas appears to closely correlate with their unique chewing habits. Mountain gorillas tend to use only one side of the jaw consistently until the teeth are totally worn so that food is no longer effectively held. The habitual chewing side of the facial bone, particularly at the facial muscle attachment site, exhibits a significant bone apposition to the extent that facial structure is often altered.50 During mastication, swallowing, and any other functional jaw movements, masticatory muscles produce force on the occlusal surface of artificial teeth, which is transmitted through the denture base and to the residual ridge. Sharry et al.51 examined bone stress patterns in dry skulls and reported that stress resulting from dentures may be transmitted over a rather wide area. However, in the patients mouth, dentures are seated on the residual ridge mucosa overlying the bone directly, which appears to primarily bear the mechanical stress. This unique environment may differentiate RRR from the common disuse atrophy concept. The keratinized edentulous mucosa can be deformed as a result of pressure from dentures15-17,52,53 and vascular alterations such as arteriosclerosis may result from long-term denture wear.5,6,54 However, the edentulous mucosa shows remarkable tolerance, and no substantial inflammatory reaction is observed.5,9,10,55-57 The mechanical stimulus applied to dentoalveolar tissue in orthodontic treatment is known to induce local bone remodeling. The synthesis of prostaglandins in periodontal tissues has been postulated to play the messenger role in linking the mechanical stimulus to the osteoclastic activity.58-60 Prostaglandins are a group of fatty acid derivatives synthesized by many different cells under stress and exert various biologic actions in the neighboring tissues, including bone resorption. The possible involvement of prostaglandin in residual ridge remodeling has been suggested. Yeh and Rodan61
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reported that repetitive mechanical stresses applied to osteoblastic cells in vitro significantly increased the prostaglandin E2 synthesis. In a separate study that used edentulous rats, the daily administration of indomethacin, an inhibitor of cyclooxygenase (an enzyme required for the prostaglandin synthesis), reduced the rate of RRR to 50% within the experimental period.62 Because the systemic delivery of prostaglandin E2 successfully reverted the inhibitory effect of indomethacin, the local synthesis of prostaglandins was postulated to mediate the residual ridge bone resorption activity.62 The direct relationship between mechanical stress and residual ridge and prostaglandin-mediated bone resorption causing severe form of RRR has not yet been fully elucidated.63 It is conceivable that biologic molecules locally synthesized in the edentulous mucosa may induce the osteoclastic activity on the surface of residual ridge alveolar bone (Fig. 2).

Osteoporosis and residual ridge remodeling

The clinical and pathophysiologic views of osteoporosis has been refined recently to the concept of Types I and II osteoporosis.64 Type I osteoporosis is defined as the specific consequence of menopausal estrogen deprivation, and characteristically presents the bone mass loss, notably in the trabecular bone. Type II osteoporosis reflects a composite of age-related changes in intestinal, renal, and hormonal function. Both cortical and trabecular bone are affected in Type II osteoporosis. In either case, one of clinical manifestations of osteoporosis is observed as less radiographic bone density. Numerous radiographs are taken in general dental practice for the screening and diagnosis of conditions not relevant to osteoporosis. However, dental radiographs might be used to screen for systemic osteoporosis as there is much evidence that the mandible reflects the quantity of bone elsewhere in the skeleton.63 For example, the dentist might suspect osteoporosis in a person with a thinned mandibular cortex.65,66 The microradiographic and histologic examinations of cadaveric mandibular bone samples from an elderly sample of edentulous persons have demonstrated that the mandibular bone undergoes considerable remodeling.3,67,68 A general radiolucency of the mandible might also be expected in those patients with systemic osteoporosis. Relationships have been found in cadaveric bone samples between the specific gravity of edentulous mandible slices and the radius.69 Densitometry of the mandible,70 dual photon absorptiometry,71 and dual energy x-ray absorptiometry (DXA)72 all demonstrated significant relationships between systemic and mandibular osteopenia. The degree of residual ridge resorption is closely related to the time since tooth extraction, and hence to
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Fig. 3. Combination of disadvantaged residual ridges (small maxillary residual ridge [Mx] and knife-edge mandibular residual ridge [Md]) is often presented in postmenopausal osteoporotic patients (A). Knife-edge residual alveolar bone (A: Boxed, and B) has been reported to associate with residual ridge mucosa with characteristic undercut (C, arrow).123

the age of the patient.73 However, the rate of residual ridge resorption has not been clearly shown to directly correlate with the bone density measured in the body of mandible and metacarpal bone.31,74-76 These studies used the height of the mandibular edentulous ridge as the measurement of residual ridge resorption. Because osteoclastic activity occurs on the surface of the residual ridge, bone resorption can result in changes of three-dimensional bone structure. The maxillary residual ridge was reported to be significantly smaller in
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postmenopausal osteoporotic women while their edentulous mandible remained the same as the age-matched controls.37 A knife-edged ridge is formed when bone resorption occurs at the labial and lingual surfaces of the residual ridge in preference to the occlusal surface. Postmenopausal women with lower bone densitometric scores exhibited a tendency to develop a knife-edge ridge in the mandible.35 These results suggested that clinically less advantageous residual ridge conditions, a combination of a small maxillary ridge and a knife-edge
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mandibular ridge, may be more prevalent in those patients with postmenopausal osteoporosis (Fig. 3). Ovariectomized animals have been intensively characterized and used in many studies as a model for human Type I osteoporosis.77,78 In ovariectomized monkeys, there is a tendency to form a knife-edge mandibular ridge as seen in postmenopausal women.79 The detailed bone remodeling in the residual ridge was examined in ovariectomized rats. By using a bone vital staining method, Hsieh et al.80,81 observed a significant increase in bone turnover and formation of immature woven bone in a trabecular area. Li and Nishimura82 reported a unique surface structure of the residual ridge alveolar bone depicted in scanning electron micrographs associated with ovariectomy pretreatment. As demonstrated in a recent study, this unique surface tissue may be influenced by the systemic estrogen level and exhibit different remodeling patterns.83 Because the residual ridge is composed of both cortical and trabecular bones, the systemic condition of Type I osteoporosis may contribute to the different remodeling rates for the cortical bone and trabecular bone. This uncoordinated remodeling pattern may result in the unique RRR pattern observed in postmenopausal female patients. The causal relationship between Type II osteoporosis and RRR has not been addressed. Recently, a line of transgenic mice was developed for the purpose of overproducing interleukin 4 (LCK-IL4 mice), which led to widespread effects on the immune system. In addition to this immunologic phenotype, characteristic bone disease involving both cortical bone and trabecular bone was observed.84 Separately developed mutant mice, the Senesent Accelerated Mouse (SAM) strain also presents senile osteoporotic bone features.85,86 The previously mentioned mouse models have great potential to be used for human Type II osteoporosis studies and may provide a long-awaited opportunity to investigate the effect of senile osteoporosis on residual ridge remodeling.

regeneration in the sheep after localized ablation. The radial arrangement of the developing bone trabeculae observed in their defects resembled the radial trabecular pattern observed on radiographs of healing tooth sockets. Coarse, birefringent collagen fibers formed a preliminary framework along which the trabeculae were oriented and were fabricated by fibroblasts, marrow reticular cells, and osteoblasts. Trabeculae were absent where this preliminary collagenous framework failed to form. Subsequent remodeling of the small primary trabeculae produced secondary trabeculae that resembled the original cancellous bone pattern. The delayed tooth socket healing often observed in poorly controlled diabetes inevitably causes a poor alveolar ridge contour. A dense network of collagen fibers normally fills the socket soon after tooth extraction, and the defect in diabetes mellitus may be due to a reduced collagen production and an absence of these fibers.92

Precursor template collagens for bone wound healing

The collagenous extraction socket matrix forms before bone formation, and it has been hypothesized that this matrix serves as a template or framework that orientates the forming bone trabeculae. Controversy surrounds the nature of the collagen molecules that provide this template function. However, because of its potentials in guiding bone wound healing, the major emphasis of current biologic studies of residual ridge remodeling is directed toward the characterization of this template stage of bone remodeling. A two-stage process of bone formation is evident in endochondral ossification, in which cartilage tissue is initially present. Chondrocytes undergo sequential histodifferentiation, which result in cellular hypertrophy and apoptosis. The remnant hypertrophic cartilage matrix is believed to provide the template scaffold for osteoblasts to precipitate bone extracellular matrix. The template cartilage matrix is eventually resorbed. Endochondral ossification is commonly seen at the growth plate of long bone, synchondrosis of the skull base, and mandibular condyle. One of the most obvious features of the healing of tooth extraction sockets is the absence of precursor cartilaginous tissue. This unique feature has been described by a general hypothesis that the tissue regeneration is considered to be a reiterated process of tissue embryogenesis. In embryos, maxillofacial bones, including tooth bearing alveolar process, is formed through intramembranous bone formation, which is different from endochondral ossification. In intramembranous bone formation examined in calvaria, the initial ectomesenchymal cells directly differentiate into osteoblasts,93 bypassing the deposition and resorption of hypertrophic cartilage matrix; osteoblasts can directly deposit osteoid tissue, which is then calcified.
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TOOTH EXTRACTION, WOUND HEALING, AND FORMATION OF THE RESIDUAL RIDGE

A specific feature of residual ridge formation is that its essential components are formed as the consequence to healing of a significant bony and mucosal wound created by tooth extraction. Histologic studies of residual ridges indicate that extraction sockets heal with active synthesis of trabecular bone. 87-89 Trabecular bone formation reaches the edge of extraction socket, whereas the osteoclastic bone resorption takes place on the surface of the residual ridge, a combination of which results in a distinct porosity on the crest of the residual ridge alveolar bone (Fig. 4).90 Aaron and Skerry91 described trabecular bone
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Fig. 4. Occlusal radiographic observations of extraction socket healing in monkey suggest that active trabecular bone formation takes place at bottom of socket, while cortical bone is subjected to bone resorption (A, 1 week after extraction of mandibular central and lateral incisors; B, 3 weeks; C, 6 weeks; D, 9 weeks; E, 12 weeks). Histology of cadaveric mandibular specimen depicting porosity at top of residual ridge alveolar bone resulted from unique bone wound healing in socket mostly with trabecular bone formation (F, Goldners trichrome staining; bar = 50 m).

It is of particular interest that recent investigations reported the transient expression of cartilaginous procollagen type II mRNA during intramembranous bone formation.94-96 Type II collagen is a major collagen type of hyaline cartilage and thus has been long considered to contribute to the structural integrity of cartilage tissue and provide a template during endochonAUGUST 1998

dral ossification. The involvement of type II procollagen mRNA in different tissues other than cartilage may suggest some as yet undefined function of type II collagen, unrelated to chondrogenesis.97 In recent years, type II collagen has been further investigated and its two alternative splicing variants of type IIA and type IIB are found to have differing cell
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Fig. 5. Diagram of alternative expression of 1(II) collagen and 1(IX) collagen genes generating tissue specific forms of collagen molecules. In type II collagen gene, exons 2 and 3 are alternatively spliced. Type IIA and IIB collagen isoforms are synthesized as result. In type IX collagen gene, two separate promoter/transcriptional start sites are found. Use of upstream promoter results in synthesis of long form type IX collagen containing amino-terminal NC4 globule, whereas activation of downstream promoter generates short form type IX collagen, which misses NC4. These alternative gene expression mechanisms appear to be used in tissue specific fashion. Cartilage tissue predominantly synthesizes combination of type IIB and long type IX collagens. During alveolar bone wound healing, it has been postulated that combination of type IIA and short type IX collagens may be synthesized.

origins.98,99 Type IIA is found in noncartilaginous tissues, whereas type IIB has a strong association with chondrocytes and cartilage tissue formation (Fig. 5).100 The expression of type II procollagen mRNA has been identified in the healing extraction sockets in experimental animals by the method of RNA transfer blot analysis and in situ hybridization.89,101 Analysis of studies on the uncomplicated healing of extraction wounds have shown that after the clot formation, granulation tissue is gradually replaced by connective tissues and later by intramembranous bone, without cartilage formation. A cluster of cells that are associated with the early socket wound healing have been shown to express type II collagen mRNA.89,101 A puzzling finding is that investigators have failed to detect the presence of protein collagen type II by way of immunohistochemical studies in actively healing extraction sockets.101 This may be suggestive of either lack of collagen type II translation or difficulties in
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detecting this protein in the healing socket. Some of the questions that need to be answered include: Which splicing variant of type II collagen is expressed in the extraction socket? What are the role of these cells in the socket healing if type II collagen protein is synthesized? Do systemic or local factors influence the gene expression pattern during socket healing?

Two-stage process of bone formation

Cartilage collagen fibrils are composed of a group of different types of collagens including type II. The surface of this fibril is associated with small collagen type IX. Because of the exposed perifibril location and the interactive peptide structure of type IX collagen, it has been postulated that type IX collagen plays a molecular bridging role in the extracellular matrix and contributes to formation of a cartilage tissue architecture.102 It has been reported that collagen type IX mRNA is also expressed in early healing stages of extraction sockets.89
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Fig. 6. Diagram of transgenic mouse generation. Target gene that has been manipulated in vitro to introduce mutation is introduced into mouse embryonic stem cells. After introduced mutant gene is incorporated into mouse chromosomes, embryonic stem cells are implanted in pseudopregnant mothers. Thus, F1 chimera population is established, which provides next generation of transgenic mice for various evaluations. In many situations, homozygous mutant mice carrying mutation in both pairs of chromosomes are used to examine effect of introduced mutation by comparison with wild type litter mates. Heterozygous mutant mice often exhibit a milder phenotype, due to existence of unaffected chromosome.

Further analyses of residual ridge remodeling in rats have revealed that the 1(IX) collagen mRNA, which was expressed in the extraction socket, was different and markedly shorter than that of cartilage. 89 The short form of type IX collagen omits the multiple exons, that encode the amino-terminal globular domain (Fig. 5).103 Therefore this alternative expression of the short form of type IX collagen, which lacks the interactive peptide structure, may explain why cartilage tissue is not assembled in the extraction socket. However, the function of the short form of type IX collagen in residual ridge remodeling remains to be clarified. Recent immunohistochemical data suggest that type IX collagen is present only in the early bone formation stages of extraction socket healing and seems to disappear during the maturation stages.104 It has been characterized in the similar transient expression of the short form of type IX collagens along with type II collagen in embryonic chicken cornea,105,106 in which the principle orthogonal fiber architecture of the mature cornea is organized according to the template tissue, primary cornea stroma.107 Both cornea and bone possess the similar orthogonal pattern of collagen fibrils. The detailed molecular assembly of type II and the short
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form of type IX collagen in bone remodeling is not elucidated. However, it is tempting to speculate that the transient matrix containing short type IX collagen may be involved in a tissue guiding role in alveolar bone repair, as used in avian eye formation.

Transgenic and inactive gene allelic manipulation in experimental animals

To understand the role of a specific molecule, one can generate animals harboring an experimentally introduced mutation to the molecule or inactivate the corresponding gene (Fig. 6). Such transgenic animals can provide a powerful tool to investigate the consequences to the missing biologic role of a specific molecule. Several transgenic mice have been generated with defective type II collagen.108,109 The introduced mutated pro 1(II) collagen chain appears to be included in a procollagen molecule and prevents folding into a stable triple helix. Transgenic mice with functionally impaired type II collagen result in chondrodysplasia with dwarfism, short and thick limbs, a short snout, a cranial bulge, a cleft palate, delayed mineralization of bone, and a severe retardation of growth for practically all bones. Because type II collagen comprises the major constituent of cartilage, the principal con233

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Fig. 7. Different extraction socket wound healing found in wild type mouse (A; bar = 50 m) and type IX collagen null transgenic mouse (B; bar = 20 m). Bone healing in transgenic mouse was characterized by loss of trabecular bone formation at bottom of extraction socket (A, arrows). However, type IX collagen knock-out mice showed loss of trabecular bone restoration pattern with relatively normal cortical bone at bottom of socket (B, arrows). (Hematoxylin and eosin staining.)

Fig. 8. Postulated bone remodeling processes that may regulate trabecular bone and cortical bone separately. Trabecular bone remodeling is hypothesized to be dependent on prior expression of type II and IX collagens, which may provide novel blueprint for trabecular bone pattern formation.

sequence of this mutation is anticipated to cause disorganization of the growth plate. However, it is interesting to note that both endochondral bones and intramembranous bones are affected by the type II collagen mutation. Nakata et al.110 reported the generation of transgenic mice harboring the minigene of 1(IX) collagen with an inframe deletion of the central domain. Some homozygous transgenic mice displayed mild proportionate dwarfism. The vertebral bodies were ovoid in shape as a result of a mild ossification defect, and the end plates in the mid-dorsal region were irregular; otherwise, the offspring of the transgenic mice survived to their maturity. After reaching maturity, onset of
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osteoarthritic changes became apparent particularly in the anterior part of the weight bearing area of the tibia. They reported that even before the histologic onset of osteoarthritis, a significant decrease in the intrinsic compressive stiffness was found in the articular cartilage of the transgenic mice. Furthermore, corneas of the transgenic offspring appeared opaque or irregular and were sometimes infiltrated by capillary vessels. The ophthalmopathy was found in about 15% of transgenic animals. These results strongly indicate that type IX collagen may play diverse biologic roles in various tissues, including localized bone remodeling. Recently, 1(IX) collagen knock-out transgenic mice were developed.111 The Neo gene was inserted in the exon 8 of the 1(IX) gene by homologous recombination, which resulted in the total inactivation of 1(IX) alleles, including both promoters. Therefore this animal model allows an investigation of the functional role of type IX collagen as a potent element for alveolar bone regeneration. Wild type and homozygous mutant mice were analyzed to elucidate the role of type IX collagen in residual ridge remodeling.112 To evaluate alveolar bone repair, the specimens were obtained at 7 days and 14 days after tooth extraction. The extraction socket of mice with inactivated 1 (IX) alleles indicated that there was a considerable retardation in the formation of the trabecular bone pattern as compared with the healing socket of the control genotypically normal mice (Fig. 7). The results indicated that the trabecular bone pattern was often disturbed in knockout mice with some formation of cortical bone within the socket. These data suggest that there may be two distinct bone remodeling processes. In the trabecular bone remodeling, the presence of type II and IX collagen
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precursors seems to be necessary. In the cortical bone remodeling, type II and IX collagen precursors may not be prerequisite (Fig. 8). Successful socket healing may use the former process, which require the transient expression of template collagens, including type II and IX.

CONCLUSIONS
The current advances in the studies of oral and maxillofacial tissue reconstruction have led to significant understanding about tissue regeneration in terminally differentiated cells, such as osteoblasts and osteoclasts, and extracellular matrix substrata. The effect of each of these essential components on tooth socket healing has been investigated extensively, but no effective therapeutic regime allowing regeneration of the residual ridge yet exists. Further molecular biologic advancement in this field may lead to the regeneration and maintenance of the alveolar bone of residual ridges, quicker osseointegration of implants and structural, and functional healing of large craniofacial bone defects.
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