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The ultrastructural distribution of two noncollagenous proteins, osteopontin (OPN) and osteocalcin (OC), originally extracted from bone matrix and proposed to play an important role in bone formation, was examined in the matrices of bone and cartilage from embryonic and postnatal chicken tibial growth plates by high-resolution immunocytochemistry using the colloidal gold technique. In bone, immunolabeling patterns using polyclonal antibodies against chicken OPN and OC were generally similar in that both showed an intense, but regionally variable, labeling of mineralized bone matrix and small mineralization loci dispersed throughout the osteoid and containing prominent condensed organic material. Unmineralized osteoid showed weak-to-moderate labeling. In the mineralized bone matrix proper, labeling was predominantly associated with amorphous, electron-dense patches of organic material among the collagen fibrils. In growth plate cartilage, both proteins first appeared related to calcified cartilage in the hypertrophic zone, although the labeling patterns were somewhat different. For OPN, gold particles were mostly associated with an organic lamina limitans-like density containing condensed, filamentous organic matrix at the periphery of small nodules and large masses of calcified cartilage, with additional moderate labeling throughout the interior of the calcified cartilage. For OC, labeling was observed over filamentous structures throughout the calcified cartilage matrix, with some, but less, labeling at the periphery. In the lowermost zones of the growth plate, the major reaction using both antibodies was found over a layer of dense, amorphous organic material at the periphery of the calcified cartilage at the future bone/calcified cartilage interface, a labeling pattern that persisted following bone deposition at these sites. OPN and to a lesser extent OC were also concentrated in cement (resting, reversal) lines. Throughout the bone and cartilage of the tibia, cells of both the osteoblastic and the osteoclastic lineages were found directly apposed to labeled surfaces and lamina limitans of organic matrix containing OPN and OC. In summary, it is concluded from the immunocytochemical data presented here that the association of OPN and OC with mineralized regions of the extracellular matrices of bone and cartilage and the accumulation of these proteins at tissue surfaces and interfaces are consistent with the hypotheses that they play a role in the extracellular mineralization process per se and/or that they may mediate cell adhesion and dynamics.
Anat Rec 1992 Dec
PMID:High-resolution immunolocalization of osteopontin and osteocalcin in bone and cartilage during endochondral ossification in the chicken tibia. 145 51

Osteocalcin, a major noncollagenous matrix protein of bone, dentin, and cementum, is found in tight association with the calcium phosphate mineral phase of these tissues. This article reviews the structural data for osteocalcin relevant to mineral adsorption. The equilibrium-binding properties for Ca2+ ions and hydroxyapatite are considered, along with the apparent physicochemical effects of osteocalcin on bone mineral dynamics. Several of osteocalcin's possible biological activities (involvement in mineralization, chemoattraction, and leukocyte elastase inhibition) are discussed in relation to the mineral-adsorption characteristics of this protein.
Anat Rec 1989 Jun
PMID:Osteocalcin-hydroxyapatite interaction in the extracellular organic matrix of bone. 254 10

Dentin may be regarded as a mineralized connective tissue. In its composition as well as its mode of formation, dentin exhibits several similarities with bone, but also definite differences. The dentin organic phase, the matrix, determines its morphology and is believed to be instrumental in the formation of the mineral phase. A fibrous web of collagen type I dominates the organic matrix. Also, minor amounts of other collagen types may be present. The noncollagenous proteins (NCPs), which constitute about 10% of the matrix, fall into several categories: phosphoproteins, Gla-proteins of the osteocalcin type as well as matrix Gla-protein, proteoglycans, different acidic glycoproteins, and serum proteins. Some of these NCPs have unique chemical compositions that give them specific properties. Dentinogenesis occurs by two simultaneous processes: the formation of a collagenous web in predentin, which is followed by the formation of the inorganic phase at the mineralization front. The composition of the predentin organic matrix differs from that of dentin, as some NCP components are secreted extracellularly just in advance of the mineralization front. In addition, some constituents of predentin seem to be metabolized. The NCPs may be important to several processes during dentinogenesis. Much evidence indicates that noncollagenous components in the matrix are instrumental in mineral formation. New data show that polyanionic NCPs, such as phosphoprotein and proteoglycans, when immobilized on a solid support, induce apatite formation under physiological conditions. These data indicate that polyanionic NCPs may function as mineral nucleators in vivo. They may also act as size and rate regulators for crystallization and promote calcium ion diffusion in the tissue. In addition, NCPs may regulate collagen fibrillogenesis.
Anat Rec 1989 Jun
PMID:Dentin matrix proteins: composition and possible functions in calcification. 267 82

Osteopontin (OPN), a noncollagenous, extracellular matrix sialoprotein found at relatively high levels in both normal and pathological mineralized tissues, is expressed by tissue-specific cells in bone, calcified cartilage, and teeth. On the other hand, a hallmark of OPN expression in pathologically mineralizing tissue, and in other soft tissues experiencing a more generalized type of necrotic injury, is the production of OPN by macrophages at the lesion site. In the present study, we have localized OPN and other noncollagenous proteins by ultrastructural colloidal-gold immunocytochemistry using a rat model in which mineralized tissue defects are surgically created in mandibular bone and teeth. The healing response was examined by immunocytochemistry and transmission electron microscopy at 10 min, 3 days and 7 days post-surgery using antibodies against OPN, bone sialoprotein, osteocalcin, bone acidic glycoprotein-75, fibronectin, and amelogenin. Whereas most of these proteins were characteristically distributed within their respective extracellular matrices as described previously, OPN was additionally observed to accumulate as a lamina limitans at surgically exposed bone and tooth surfaces, as well as at the surface of particulate, mineralized tissue debris. Intracellular labeling of the Golgi apparatus and secretory granules of macrophages at the lesion site demonstrated that OPN production by macrophages was a prominent secretory event of the inflammatory response during wound healing in mineralized tissues. Pseudopodal and lamellipodal cytoplasmic extensions of macrophages were observed in direct contact with the OPN-containing lamina limitans at these surfaces. Particulate, calcified debris internalized by macrophages also displayed a prominent surface "coating" of OPN. In conclusion, our interpretation of the present data is that OPN secreted by macrophages may serve as a macrophage adhesion protein, and where concentrated at the surface of small particulate, mineralized tissue debris, may act as an opsonin, thereby facilitating cell adhesion and phagocytosis by macrophages, a process likely mediated by integrin-binding, signal transduction, and cytoskeletal restructuring.
Anat Rec 1996 Jun
PMID:Secretion of Osteopontin by macrophages and its accumulation at tissue surfaces during wound healing in mineralized tissues: a potential requirement for macrophage adhesion and phagocytosis. 876 75

Enzymatic digestion of bone tissue potentially releases a mixture of precursor, differentiating, and mature cells. Conceptually, early fetal osteogenic tissue should provide a more uniform population of cells than late embryonic or newborn bone in which cells have already differentiated. In this context, we have applied sequential enzymatic digestion to obtain and culture cells from 15-16-day fetal rat cranial tissue, a developmental age where deposition of bone matrix has not yet started at this site. These cultures were compared with those of osteogenic cells isolated from newborn rat calvariae and grown under similar conditions. Matrix production and composition were examined by colloidal gold immunocytochemistry using antibodies to bone sialoprotein (BSP), osteocalcin (OC), and osteopontin (OPN). The plated cells formed mineralized nodules by day 14. The presence of mineral was determined by von Kossa staining and backscattered electron imaging (BEI), and the accumulation of calcium and phosphorus within the nodules was demonstrated by X-ray microanalysis and elemental mapping. At early time intervals, cells were generally cuboidal in shape and showed a well-developed Golgi apparatus, which occasionally was immunoreactive for OPN. Labeling for BSP and OPN was found over mineralization foci and electron-dense material within, and at the periphery, of larger mineralized masses and over accumulations of afibrillar matrix at the dish surface. Osteocalcin immunoreactivity was also associated with electron-dense portions of the bone-like matrix. These data demonstrate the potential of presumptive fetal rat calvarial cells to form a bone-like matrix in vitro and suggest that the assembly and mineralization pattern show similarities to the process of intramembranous ossification. Such a culture system is of interest not only for studying cellular and matrix events of bone formation, but also factors which influence mesenchymal cells in committing themselves to the osteogenic pathway.
Anat Rec 1998 12
PMID:Morphological and immunocytochemical characterization of primary osteogenic cell cultures derived from fetal rat cranial tissue. 984 6

Although it is known that skeletal bone depletion occurs during antler growth in deer, it is not clear whether repletion of the skeleton takes place before or after completion of antler development. This study attempted to correlate repeated scanning electron microscopic measures of ilium and rib bone porosity from six approximately 2-monthly biopsy samples (using back-scattered imaging) and biochemical markers of bone turnover (serum hydroxyproline and osteocalcin concentrations) taken for 11 months with antler growth in six red deer stags. No changes were detected in ilium samples but changes in porosity of rib bones and an elevation of the biochemical markers indicated that skeletal depletion occurred during the antler growth period. However, the decrease in rib bone porosity and decline in markers of bone turnover took place before completion of antler growth, indicating that a considerable amount of skeletal repletion could have occurred whilst antlers were also undergoing bone accretion. This latter finding extends the current view of antler growth being accompanied by a form of reversible osteoporosis in the skeleton by showing that there is a period when the antlers and skeleton are both undergoing net bone formation.
Anat Rec 1999 09 01
PMID:Bone turnover associated with antler growth in red deer (Cervus elaphus). 1045 81

The periosteum contains osteoprogenitors that differentiate to osteoblasts in bone growth or repair. Our previous studies suggested the hypothesis that the physical contact of the periosteum with the bone matrix is requisite for the differentiation of osteoblasts. To test the hypothesis, the present study was designed to investigate how the contact between the periosteum and the bone matrix influences the osteoblastic differentiation of periosteal cells with establishing a new experimental model in vivo. Differentiation of osteoblasts was assessed by gene expression of type I collagen, osteocalcin and bone sialoprotein using in situ hybridization. A barrier was designed to prevent periosteal cells from contacting the bone matrix using the membrane filter. The membrane filter was inserted surgically between the surface of rat parietal bone and the periosteum after being punched out with pin holes. Periosteal cells were allowed to contact with the bone surface only through the pin holes. The pin hole was filled with cells derived from the periosteum 1 week after inserting the filter. Differentiation of osteoblasts in week 2 and noticeable bone formation in week 3 were identified on the bone surface only under the pin hole but not under the filter. The present study demonstrated that the physical contact with the bone matrix promotes osteoblastic differentiation of periosteum-derived cells in vivo.
Anat Rec 2001 09 01
PMID:Osteoblastic differentiation of periosteum-derived cells is promoted by the physical contact with the bone matrix in vivo. 1150 73

Our previous studies suggested that a part of bone extracellular matrix (ECM) molecules are degraded and remodeled during embryonic bone formation. In contrast, little is known about ECM remodeling in postnatal appositional bone formation. The present study was designed to investigate expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during experimentally initiated appositional bone formation in rats. Expressions of ECM molecules, MMPs, and TIMPs were examined using in situ hybridization. Osteoblasts and osteocytes expressed MMP2 and -8, TIMP1, -2, and -3, as well as type I collagen, osteopontin, and osteocalcin in the course of the appositional bone formation, while they showed few transcripts of MMP13. The results indicated that while osteoblasts and osteocytes in the apposed bone produce ECM molecules, they degrade ECM molecules with MMPs and regulate the degradation by inhibiting the activity of MMPs using TIMPs. Osteoblasts and osteocytes may reorganize the ECM composition to mature the bone matrix in appositional bone formation.
Anat Rec A Discov Mol Cell Evol Biol 2004 Apr
PMID:Osteoblasts and osteocytes express MMP2 and -8 and TIMP1, -2, and -3 along with extracellular matrix molecules during appositional bone formation. 1505 53

It has been generally accepted that bone morphogenetic protein-2 (BMP-2) can induce osteogenesis in skeletal muscles via endochondral ossification. However, it is not clear how the ossification process occurs after the BMP-2 gene transfer to skeletal muscles in rats using in vivo electroporation. In this study, we evaluated the ossification process by BMP-2 gene transfer using in vivo electroporation. The gastrocnemius muscles of Wistar rats were injected with human BMP-2 gene expression vector (pCAGGS-BMP-2), followed by electroporation under the condition of 100 V, 50 msec per 1 sec, x8. Light and electron microscopic and radiographic analyses were performed at 1, 3, 5, 7, and 10 days after treatment. At 7 days, no sign of cartilage and/or bone formation was detected. However, at 10 days after in vivo electroporation, soft X-ray analysis revealed small lucent areas around the plasmid-injected region. Clusters of both cartilage tissues, leading to endochondral ossification and intramembranous bones of various sizes, were observed between muscle fibers. RT-PCR detected osteocalcin mRNA, showing bone formation at 10 days. Our findings strongly suggest that BMP-2 gene transfer using in vivo electroporation induces not only endochondral ossification but also intramembranous ossification.
Anat Rec A Discov Mol Cell Evol Biol 2005 Dec
PMID:Human BMP-2 gene transfer using transcutaneous in vivo electroporation induced both intramembranous and endochondral ossification. 1624 97

The study examined the expression of matrix metalloproteinases (MMPs), type I collagen and osteocalcin during bone healing in a rat calvarial experimental defect model. Twelve-week-old male Wistar rats were used. A full-thickness standardized trephine defect was made in the parietal bone, with the rat under anesthesia. RNA was extracted from tissue that filled the original bone defect on days 1 and 3 and in weeks 1, 2, 3, 5, 8, 10, 12, 18, and 24 and processed for quantitative analysis of expression of type I collagen, osteocalcin and matrix metalloproteinases (MMPs) 2, 8, and 13 by using real-time polymerase chain reaction. Alternatively, the rats were fixed by perfusion through the aorta and resected calvaria were processed for in situ hybridization for these molecules. The expression of type I collagen, osteocalcin and MMPs 2 and 13 increased toward week 2 and decreased thereafter, whereas the expression of MMP 8 was the highest on day 1. The mRNA transcripts of type I collagen and osteocalcin were localized in osteoblasts and osteocytes, some of which expressed MMPs 2, 8, and 13. Osteoblasts and osteocytes may play a role in the remodeling of extracellular matrices with MMPs during healing of a defect in bone.
Anat Rec (Hoboken) 2008 Aug
PMID:Quantitative analysis and localization of mRNA transcripts of type I collagen, osteocalcin, MMP 2, MMP 8, and MMP 13 during bone healing in a rat calvarial experimental defect model. 1861 87


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