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M C Meikle

Publications and source records attributed to M C Meikle.

At least 37 records · Page 2Linked to original sources
PubMed1995

Matrix metalloproteinases and TIMP-1 localization at sites of osteogenesis in the craniofacial region of the rabbit embryo.

BACKGROUND: The matrix metalloproteinases (MMPs) are a family of closely related enzymes, the principal members being the collagenases, gelatinases, and stromelysins. They are synthesized and secreted by connective tissue cells and are capable of degrading all the components of connective tissue matrices at physiological pH. METHODS: Patterns of synthesis and distribution of MMPs and their inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1), are documented in the craniofacial region at sites of bone formation during both intramembranous (e.g., calvaria, maxilla, and mandible) and endochondral ossification (e.g., cartilaginous cranial base and synchondroses) using indirect immunolocalization. RESULTS: MMPs and TIMP-1 were detected both as bright intracellular accumulations, indicating active synthesis, and as diffuse matrix-bound extracellular deposits. Gelatinase-A had an extensive distribution in osteogenic tissues and was detected both in cells of the periosteum and spongiosum and as extracellular deposits in the osteoid layer of newly formed bone. In addition, gelatinase-AB synthesis was detected in osteoclasts. All regions of the early cartilaginous cranial base produced MMPs and TIMP-1, and synthesis continued in the established synchondrosis. MMPs and TIMP-1 were also documented in early tooth germs and in Meckel's cartilage. CONCLUSIONS: These data document a prominent role for MMPs, and in particular gelatinase-A, in mediating matrix degradation during osteogenesis. Their detection in tooth germs and Meckel's cartilage further indicates a role for MMPs and TIMP-1 in matrix turnover during morphogenesis.

Animals↗
PubMed1995

The synthesis of collagenase, gelatinase-A (72 kDa) and -B (95 kDa), and TIMP-1 and -2 by human osteoblasts from normal and arthritic bone.

Bone resorption is a complex multistep process that involves removal of both the organic and mineral constituents of bone matrix by proteolytic enzymes synthesized by osteoblasts and osteoclasts. To further understand the role of matrix metalloproteinases (MMPs) and their specific inhibitors TIMPs (tissue inhibitor of metalloproteinases) in this process, human osteoblasts were obtained by sequential enzymatic digestion from samples of bone from normal donors and patients with various forms of arthritis; first passage cells were used in all experiments and cultured on a type I collagen substratum. Collagenase was detected by an ELISA in supernatants from unstimulated osteoblasts (range 12-730 ng/mL), although the levels did not appear to bear any relationship to the age or clinical status of the patient; treatment with parathyroid hormone (PTH; 2 units/mL) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 10 ng/mL] had no added effect, but mononuclear cell conditioned medium (MCM; 5% v/v) and interleukin-1 alpha (IL-1 alpha; 1 ng/mL) both stimulated collagenase synthesis, in the case of MCM by two orders of magnitude. TIMP-1 was detected in unstimulated cultures by an ELISA (range 320-590 ng/mL), the mean level being three-fold greater than for collagenase and was stimulated by 1,25(OH)2D3 and MCM treatment. Degradation studies showed that, over a 120 h culture period, one third of the collagen substratum was degraded by unstimulated cells. PTH and 1,25(OH)2D3 had no effect on this endogenous level of lysis, but addition of MCM and IL-1 alpha resulted in a significant increase in collagen degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Osteoblasts mediate insulin-like growth factor-I and -II stimulation of osteoclast formation and function.

Insulin-like growth factor-I (IGF-I) and IGF-II have powerful, well defined effects on osteoblastic cells, stimulating their proliferation and inducing collagen synthesis, but the role of IGF-I and -II in modulating osteoclast differentiation and activity remains unclear. We first examined the bone-resorptive effects of IGF-I and IGF-II by assessing 45Ca2+ release from neonatal mouse calvarial bones. Both IGFs dose dependently stimulated bone resorption, with an EC50 of 8 x 10(-9) M for IGF-I and 2 x 10(-8) M for IGF-II. We then tested the effects of the IGFs on bone resorption by rat isolated osteoclasts cultured on ivory slices. Neither IGF-I nor IGF-II stimulated isolated osteoclast activity. However, in the presence of either primary mouse osteoblasts or human osteosarcoma MG 63 cells, both IGFs enhanced osteoclast resorptive activity, with an EC50 of 5 x 10(-10) M for IGF-I and 10(-9) M for IGF-II. Stimulation was not mediated by BALB/c/3T3 cells, a nonosteoblastic cell line. The effects of the IGFs were blocked by alpha IR-3, an antibody to the type I IGF receptor, but not by beta-galactosidase, a lysosomal enzyme that competes with IGF-II for the type II IGF receptor. We then examined the effects of the IGFs on the formation of osteoclast-like multinucleate cells (MNCs) in mouse bone marrow cultures. IGF-I and -II dose dependently increased the number of tartrate-resistant acid phosphatase (TRAP)-positive MNCs, although their effects were less than that of 1,25-dihydroxyvitamin D3 (a hormone that induces osteoclast differentiation). No TRAP-positive MNCs appeared in the absence of these hormones. Like authentic osteoclasts, the TRAP-positive MNCs formed in response to IGF-I and -II bound [125I]salmon calcitonin. When mouse bone marrow cells were cultured on ivory slices in the presence of either IGF-I or IGF-II for 10 days, numerous resorption lacunae were formed. beta-Galactosidase had no effect on IGF-mediated osteoclast formation. These results are strong evidence that both IGF-I and IGF-II stimulate bone resorption in vitro by enhancing osteoclast formation and function. Our data also suggest that the IGFs act through the intermediary of osteoblastic cells to stimulate osteoclast activity and that the type I, but not the type II, IGF receptor is involved in their responses. We propose that the local production of IGF-I and IGF-II may modulate both osteoblast-osteoclast interactions and osteoclast formation and play an important role in bone remodeling.

Acid Phosphatase↗
PubMed1994

The purification and partial characterization of bone resorptive polypeptides from bovine bone matrix.

Matrix proteins were extracted from bovine cortical bone with EDTA/Tris-HCl under non-dissociative conditions at neutral pH. Four distinct bone resorptive proteins with molecular masses of 14, 25, 29 and 40 kDa were purified and partially characterized using an in vitro neonatal mouse calvarial assay and a growth factor assay using BALB/c/3T3 cells. The 14 kDa protein was purified by anion exchange chromatography (Mono Q) and gel filtration (Superdex 75HR) using FPLC (fast protein liquid chromatography); this factor stimulated the proliferation of MCF-7 human breast cancer cells, a bioassay which is specific for the insulin-like growth factors (IGFs). The 25, 29 and 40 kDa proteins were purified by sequential chromatography as follows: anion-exchange (Mono Q), heparin-Sepharose, hydroxyapatite, concanavalin A-Sepharose, phenyl-Superose, reversed phase high performance liquid chromatography (HPLC) and sodium dodecylsulfate polyacrylamide gelelectrophoresis (SDS-PAGE). The 25 kDa protein was identified as TGF-beta by its inhibitory effect on the proliferation of mink lung cells. The 40 kDa protein enhanced the formation of multinucleate tartrate-resistant acid phosphatase positive cells in a murine bone marrow differentiation assay, but was without effect in an isolated osteoclast assay and had no growth factor activity; this protein is likely to be a colony stimulating factor. The 29 kDa protein was also without growth factor activity; it was, however, able to stimulate bone resorption in the isolated osteoclast assay, suggesting a direct action in osteoclast function. The 29 and 40 kDa proteins may be osteoblast gene products that have been sequestrated by the bone matrix in a similar fashion to TGF-beta and the IGFs. This is the first report of proteins isolated from bone matrix which directly stimulate osteoclast differentiation and activity.

Animals↗
PubMed1994

Rabbit calvarial osteoblasts in culture constitutively synthesize progelatinase-A, and TIMP-1 and TIMP-2.

Defining the TIMPs (tissue inhibitors of metalloproteinases) produced by non-human bone cells is important because animal models and cells are used extensively for research on bone resorption, and because TIMP-2 can bind to and prevent activation of progelatinase-A. By zymography we show that rabbit calvarial osteoblasts in culture constitutively synthesize TIMP-2 in addition to TIMP-1 and progelatinase-A. Previously we found that human osteoblasts produced only low levels of TIMP-2 under any conditions. We also show that stimulated rabbit osteoblasts can degrade a type I collagen film even though both TIMPs are being synthesized.

Animals↗
PubMed1994

Inhibition of bone resorption by selective inactivators of cysteine proteinases.

Inactivators of cysteine proteinases (CPs) were tested as inhibitors of bone resorption in vitro and in vivo. The following four CP inactivators were tested: Ep475, a compound with low membrane permeability which inhibits cathepsins B, L, S, H, and calpain; Ep453, the membrane-permeant prodrug of Ep475; CA074, a compound with low membrane permeability which selectively inactivates cathepsin B; and CA074Me, the membrane-permeant prodrug of CA074. The test systems consisted of 1) monitoring the release of radioisotope from prelabelled mouse calvarial explants and 2) assessing the extent of bone resorption in an isolated osteoclast assay using confocal laser microscopy. Ep453, Ep475, and CA074Me inhibited both stimulated and basal bone resorption in vitro while CA074 was without effect; the inhibition was reversible and dose dependent. None of the inhibitors affected protein synthesis, DNA synthesis, the PTH-enhanced secretion of beta-glucuronidase, and N-acetyl-beta-glucosaminidase, or the spontaneous release of lactate dehydrogenase. Ep453, Ep475, and CA074Me dose-dependently inhibited the resorptive activity of isolated rat osteoclasts cultured on bone slices with a maximal effect at 50 microM. The number of resorption pits and their mean volume was reduced, whilst the mean surface area remained unaffected. Again, CA074 was without effect. Ep453, Ep475, and CA074Me, but not CA074, when administered subcutaneously at a dose of 60 micrograms/g body weight inhibited bone resorption in vivo as measured by an in vivo/in vitro assay, by about 20%. This study demonstrates that cathepsins B, L, and/or S are involved in bone resorption in vitro and in vivo. Whilst cathepsin L and/or S act extracellularly, and possibly intracellularly, cathepsin B mediates its effects intracellularly perhaps through the activation of other proteinases involved in subosteoclastic collagen degradation.

Animals↗
PubMed1994

Effect of poly DL-lactide--co-glycolide implants and xenogeneic bone matrix-derived growth factors on calvarial bone repair in the rabbit.

Polymer implant discs composed of 50:50 poly DL-lactide-co-glycolide (molecular weight about 9000) were used to repair 5 mm calvarial defects in 2 kg rabbits and osseous repair compared to spontaneous healing (control). After 4 weeks the implants had undergone substantial degradation with little evidence of residual polymer. The extent to which the defects had been replaced by bone showed individual variation. In some animals a layer of bone with normal cancellous architecture had bridged the defect, but at no time was bone observed in intimate contact with the polymer matrix, suggesting that the material had acted as a tissue spacer rather than an osteoconductive substrate. Non-osseous tissue consisted of a highly vascular fibrous connective tissue containing variable numbers of inflammatory cells. In some sites numerous macrophages and multinucleate giant cells were observed, the majority of which were shown by immunocytochemistry to be MHC class II-positive. Histomorphometric analysis demonstrated no statistically significant difference in osseous repair between control and polymer implant groups after 1, 2 or 3 months. Incorporation of bone matrix proteins extracted from bovine cortical bone into the discs, however, provoked a cellular and humoral immune response which had a significant inhibitory effect on osseous repair. These data suggest, first, that while synthetic polymers have potential as bone graft substitutes, improvements in their performance in vivo are needed and, second, it is advisable to use allogeneic proteins in rabbit models of bone regeneration.

Animals↗
PubMed1994

Resorbable synthetic polymers as replacements for bone graft.

The potential of resorbable synthetic polymers derived from the poly(alpha-hydroxy acids), poly(lactide) and poly(glycolide), to fulfill a role as bone graft substitutes is reviewed. The various elements of the relationship between the degradation behaviour of resorbable implants and polymer synthesis and chain structure, implant morphology, processing and dimensions have been defined. The production of resorbable polymeric implants has been extensively documented so as to provide a wide basis for selection of an appropriate manufacturing technique. The key requirement of implant dimensional stability over the early stages of bone healing is emphasised so as to provide a stable surface on which osteoblasts and/or their precursor cells may migrate and secrete bone matrix. Minimisation of the content of slow resorbing polymers such as poly(L-lactide) is recommended, consistent with retention of an adequate implant degradation characteristic. The review concludes with a summary of alternative resorbable polymers such as the polyphosphazines which are interesting candidate materials for bone repair and reconstruction.

Biomechanical Phenomena↗
PubMed1994

Immunolocalization of matrix metalloproteinases and TIMP-1 (tissue inhibitor of metalloproteinases) in human gingival tissues from periodontitis patients.

The matrix metalloproteinases (MMPs) collagenase, gelatinase A (72 kDa gelatinase), stromelysin, and their specific inhibitor TIMP-1 (tissue inhibitor of metalloproteinases), were immunolocalized using specific polyclonal antisera in gingival tissues from 21 patients with chronic inflammatory periodontal disease. Monoclonal antibodies against macrophages (Leu-M5), B cells (Leu-14), helper T cells (OKT4), suppressor T cells (OKT8) and the HLA-DR epitope were also used to identify leukocyte subsets. MMPs were observed in connective tissues at sites that histologically showed signs of remodelling. The number and distribution of positive cells varied widely, however, not only between individual biopsy specimens, but also within the same specimen. The same was true for the composition and distribution of the inflammatory cell infiltrate. Moreover, although there was a positive correlation between the number of MMP-producing cells and the severity of inflammation in some specimens, for others with comparable leukocyte subset scoring the number was reduced and sometimes absent altogether. Cells secreting MMPs were fibroblasts, macrophages and epithelial cells. It was not possible to determine unequivocally whether a MMP-positive cell within the connective tissue was a fibroblast or a macrophage, since the antisera recognise both fibroblast and macrophage MMPs and the different fixation requirements for MMPs (4% paraformaldehyde) and Leu-M5 (acetone) precluded co-localization on the same section. TIMP-1 was immunolocalized within connective tissue cells at sites of tissue remodelling. Our results support the hypothesis that tissue-derived MMPs may be involved in tissue remodelling in periodontal disease and conclusively demonstrate that epithelial cells may be involved as well as connective tissue cells.

Antibodies, Monoclonal↗
PubMed1994

Connective tissue degradation in health and periodontal disease and the roles of matrix metalloproteinases and their natural inhibitors.

Connective tissue remodeling is essential for normal growth and development, and many diseases have long been associated with the breakdown of the collagenous matrix of bone, cartilage, and related tissues. Recent work has established that members of the family of matrix metalloproteinases (MMPs) are key enzymes in matrix degradation. They function at neutral pH and can digest synergistically all the matrix macromolecules. Biochemical and cloning studies indicate that there are three major groups, collagenases, gelatinases, and stromelysins. Naturally occurring inhibitors, TIMPs (Tissue Inhibitors of MetalloProteinases), are important controlling factors in the actions of MMPs, and tissue destruction in disease processes often correlates with an imbalance of MMPs over TIMPs. The major inhibitor is TIMP-1 (or TIMP), a 30-kDa glycoprotein that is synthesized by most cells. The expression of MMPs and TIMPs by cells is regulated by many cytokines (particularly interleukin-1, IL-1), growth factors, and hormones, some of which are specific to cell type and others that are ubiquitous (e.g., transforming growth factor beta, TGF-beta). One way in which pathogenic organisms might mediate tissue degradation in periodontal diseases is through the ability of cell wall antigens to stimulate cytokine production by circulating mononuclear cells. These would then induce MMP synthesis by resident gingival cells, thereby initiating degradative events. Direct in vivo evidence for the source of collagenase and other MMPs in periodontal tissues is limited. By using specific polyclonal antibodies and indirect immunofluorescence, we could demonstrate the presence of collagenase, stromelysin-1, gelatinase A, and TIMP in human gingival biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Connective Tissue↗
PubMed1994

The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts.

We have compared the effects of a general matrix metalloproteinase (MMP) inhibitor (CT435) with those of a concentration-dependent specific gelatinase inhibitor (CT543; Ki < 20 nM) on bone resorption in vitro. The test systems consisted of measuring: (i) the release of 45Ca2+ from prelabelled mouse calvarial explants; (ii) the release of 45Ca2+ from prelabelled osteoid-free calvarial explants co-cultured with purified chicken osteoclasts; and (iii) lacunar resorption by isolated rat osteoclasts cultured on ivory slices. Both CT435 and CT543 dose-dependently inhibited the release of 45Ca2+ from neonatal calvarial bones stimulated by either parathyroid hormone or 1,25-dihydroxyvitamin D3. Moreover, CT543 produced a 40% inhibition at a concentration (10(-8) M) selective for the inhibition of human gelatinases A and B. CT435 (10(-5) M) and CT543 (10(-5) M) partially inhibited the release of 45Ca2+ from osteoid-free calvarial explants by chicken osteoclasts with a maximum of approximately 25% for unstimulated cultures, and approximately 36% for cultures stimulated by interleukin-1 alpha (IL-1 alpha; 10(-10) M). Neither inhibitor prevented lacunar resorption on ivory by unstimulated rat osteoclasts, but the compounds produced a partial reduction in both the number and total surface area of lacunae in IL-1 alpha-stimulated cultures, with maximal action at 10(-5) M. Neither of the inhibitors affected protein or DNA synthesis, nor the IL-1 alpha-stimulated secretion of the lysosomal enzyme beta-glucuronidase. Immunocytochemistry demonstrated that isolated rabbit osteoclasts constitutively expressed gelatinase A and synthesized gelatinase B, collagenase and stromelysin, as well as the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) following IL-1 alpha stimulation. These experiments have shown that in addition to collagenase, gelatinases A and B are likely to play a significant role in bone resorption. They further suggest that MMPs produced by osteoclasts are released into the sub-osteoclastic resorption zone where they participate in bone collagen degradation.

Animals↗
PubMed1994

Regional and temporal changes in the synthesis of matrix metalloproteinases and TIMP-1 during development of the rabbit mandibular condyle.

Connective tissues synthesise and secrete a family of matrix metalloproteinases (MMPs; collagenases, gelatinases and stromelysins) capable of degrading all the components of connective tissue matrices at physiological pH. We document the patterns of synthesis and distribution of MMPs and the tissue inhibitor of metalloproteinases-1 (TIMP-1) within the developing rabbit mandibular condyle using immunofluorescence microscopy. MMPs and TIMP-1 were detected both as bright intracellular accumulations within Golgi vesicles and also as diffuse matrix-bound extracellular deposits. Cells in the articular zone, proliferative zone, condylar cartilage and bone of the mandibular ramus were shown to produce all 3 classes of MMPs and TIMP-1 with the exception of stromelysin, which was not synthesised by cells of the bone of spongiosum. Temporal synthesis of MMPs and TIMP-1 within these regions varied during the period 18 d postcoitum to 14 d postnatum. Our results document unique patterns of MMP and TIMP-1 synthesis during embryonic and early postnatal development of condylar cartilage and support the concept that cells synthesise and secrete MMPs and TIMP-1 before undergoing proliferation and hypertrophy. A comparison of these results with data in the rabbit growth plate show many similarities, but some differences exist that probably reflect differences in the modes of growth of the 2 cartilages.

Animals↗
PubMed1993

Inhibition of stimulated bone resorption in vitro by TIMP-1 and TIMP-2.

Recombinant human TIMP-1 and TIMP-2 (tissue inhibitors of metalloproteinases) inhibited bone resorption induced by either parathyroid hormone or 1,25-dihydroxyvitamin D3 in cultured neonatal mouse calvariae. The inhibition was reversible, dose-dependent and complete at 1 microgram/ml inhibitor concentration. TIMP-2 was more potent than TIMP-1. TIMP-1 and TIMP-2 also inhibited basal bone resorption. Neither metalloproteinase inhibitor affected protein synthesis, DNA synthesis, the PTH-enhanced secretion of beta-glucuronidase or the spontaneous release of lactate dehydrogenase. These results suggest that endogenous TIMPs play a central role in regulating both physiological and pathological bone resorption.

Animals↗
PubMed1993

Pertussis toxin-sensitive activation of phospholipase A2 can be resolved from phosphoinositidase C in primary cultures of mouse osteoblasts using indomethacin.

Recent work has established that various bone-resorbing hormones are able to activate phosphoinositide metabolism as well as eicosanoid production in osteoblast-like cells, although the relationship between these pathways is unclear. We used pertussis toxin and indomethacin to inhibit the stimulation of [3H]arachidonic acid release and [3H]phosphoinositide turnover caused by treating primary cultures of mouse osteoblasts with fetal calf serum. We found (1) that pertussis toxin and indomethacin each inhibited both pathways and (2) that although pertussis toxin inhibited [3H]arachidonic acid release to a greater extent than indomethacin, [3H]inositol phosphate accumulation was inhibited rather more effectively by indomethacin. These data suggest that whereas ligands in fetal calf serum activate [3H]arachidonic acid release largely directly via the action of a pertussis-sensitive G protein, activation of phosphoinositidase C is indirect, being substantially dependent upon eicosanoid production. These experiments suggest that serial activation of phospholipase A2 and phosphoinositidase C may occur in osteoblasts and that only the former enzyme is regulated by a pertussis toxin-sensitive G protein.

Adenosine Diphosphate Ribose↗
PubMed1993

Preliminary characterization of porcine bone marrow stromal cells: skeletogenic potential, colony-forming activity, and response to dexamethasone, transforming growth factor beta, and basic fibroblast growth factor.

Neonatal pig bone marrow stromal cells (PBMSC) were tested in vivo and in vitro to establish their use as a large-animal model for the study of skeletogenesis. When implanted in diffusion chambers in athymic mice for 6-8 weeks, both freshly isolated pig bone marrow and passage 2 PBMSC formed partially mineralized cartilage, bone-like material, and fibrous tissue. The cartilage showed metachromatic, perilacunar staining with toluidine blue and safronin O, alcian blue staining for chondroitin and keratan sulfate, and intense immunostaining for type II collagen. Osteocalcin was immunolocalized to the mineralized regions, consistent with the formation of bone. Alkaline phosphatase was primarily observed in cell layers at boundaries between tissue types. Unstimulated monolayer cultures of PBMSC produced type I but not type II collagen, responded to dexamethasone (10(-8) M) with a 1.7-fold increase in alkaline phosphatase activity, and were stimulated to divide by basic fibroblast growth factor (1.5-fold; EC50 1 ng/ml). Transforming growth factor beta (TGF-beta) blocked both dexamethasone-induced alkaline phosphatase expression (EC50, 1 ng/ml of TGF-beta) and the mitogenic effects of bFGF (EC50 0.06 ng/ml of TGF-beta). When incubated for 10-14 days in medium containing dexamethasone, beta-glycerophosphate and ascorbate PBMSC formed mineralized nodules. Calcification occurred in the middle of the aggregates and was associated with intensely alkaline phosphatase positive cells and a dense type I collagen-rich matrix. PBMSC also displayed colony-forming unit-fibroblastic activity, with approximately 1 in 80 of the plated cells formed colonies > 128 cells over 14-21 days. PBMSC therefore mimic the known activities of stromal cells from other species, including the human, suggesting that they are a valid model for skeletal research.

Alkaline Phosphatase↗
PubMed1993

Bone-derived growth factor release from poly(alpha-hydroxy acid) implants in vitro.

Matrix proteins were extracted from bovine cortical bone and polymer implant discs (13 mm x 2 mm composed of 50:50 poly DL-lactide-co-glycolide; mol. wt. approximately 9000) prepared by compression moulding granules with lyophilized bone matrix extracts (BMX) 10.1 (w/w). BMX-containing polymers were cultured for 5 wk in either serum-free Dulbecco's modification of Eagle's medium (DMEM) or phosphate buffer, and growth factor activity released into the media assayed by its ability to stimulate the proliferation of murine fibroblast BALB/c/3T3 cells. Approximately 60-75% of the biological activity was released during the first week of culture; however, less than half of the growth factor units originally incorporated into the implants retained biological activity. Scanning electron microscopy revealed the development of significant internal porosity by week 2; the size of the channels, pores and surface openings suggested they were of the right order for bone ingrowth. These preliminary findings suggest that poly(alpha-hydroxy acid) polymers containing bone-derived growth factors could have potential for stimulating osseous regeneration in vivo.

3T3 Cells↗
PubMed1993

Recent advances in understanding mechanically induced bone remodeling and their relevance to orthodontic theory and practice.

This review highlights recent developments in bone cell biology, evaluates previous research, and offers future direction toward improving our understanding of events that mediate orthodontic tooth movement. The in vivo and in vitro models that have been developed to examine the responses of connective tissues and how they have contributed to our understanding of the mechanisms involved in mechanically induced bone remodeling are discussed in detail. Osteoblasts are now recognized as the cells that control both the resorptive and the formative phases of the remodeling cycle, and receptor studies have shown them to be the target cells for resorptive agents in bone. The osteoblast is perceived as a pivotal cell, controlling many of the responses of bone to stimulation with hormones and mechanical forces. It is apparent that not all the cellular responses induced by mechanically deformed tissues can be explained by the current paradigm emphasizing the importance of prostaglandin production and cAMP elevation; the mobilization of membrane phospholipids giving rise to inositol phosphates offers an alternative second messenger pathway. It is also argued from circumstantial evidence that changes in cell shape produce a range of effects mediated by membrane integral proteins (integrins) and the cytoskeleton, which may be important in transducing mechanical deformation into a meaningful biologic response.

Animals↗