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PubMed2001

Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development.

Amylin and calcitonin gene-related peptide (CGRP) are homologous 37 amino acid peptides that are found in the circulation. Both peptides belong to the calcitonin family. Similar to calcitonin, amylin and CGRP inhibit osteoclast activity, although they are much less potent than calcitonin. Calcitonin is known to act on the latter stages of osteoclast development, inhibiting the fusion of committed preosteoclasts to form mature multinucleated cells; however, whether or not calcitonin acts earlier in the formation of the precursor osteoclasts is controversial. The question of osteoclast development has never been examined with respect to amylin and CGRP. These issues are addressed in the present study. We studied the effects of calcitonin (salmon and rat), amylin (human and rat), and CGRP (human and rat) in mouse bone marrow cultures stimulated to generate osteoclasts using 1alpha,25-dihydroxyvitamin D3. Calcitonin dose-dependently decreased the numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells as well as TRAP-positive mono-/binucleated cells at concentrations >10(-13) mol/L. Amylin and CGRP showed similar effects at concentrations >10(-9) mol/L. In addition, calcitonin substantially reduced the ratio of TRAP-positive multinucleated to mono-binucleated cells, indicating an effect on fusion of osteoclast precursors. The present data establish that this family of peptides not only acts on mature osteoclasts but also inhibits their development in bone marrow cultures. This activity is shared by amylin and CGRP. The much greater potency of calcitonin than amylin and CGRP is consistent with the action of these peptides being mediated by calcitonin receptors.

Amyloid↗

PubMed2001

Interleukin-4 and interleukin-13: bidirectional effects on human osteoclast formation.

Osteoclasts are cells that resorb bone; they derive from macrophage colony-stimulating factor (M-CSF)-dependent hematopoietic precursors in the presence of soluble activator of NFkappaB ligand (sRANKL). Because transforming growth factor (TGF)-beta, a macrophage deactivator, enhances osteoclast formation we hypothesized that interleukin (IL)-4 and IL-13, also macrophage deactivators, should exert a similar effect. However, IL-4 and IL-13 have been reported as suppressors of murine osteoclast formation. In contrast to the effect of these molecules on murine osteoclast formation, IL-4 and IL-13 were found to be powerful inducers of osteoclast formation and bone resorption when added to human peripheral blood mononuclear cell (PBMC) cultures for 4 days. This stimulatory effect was only observed in cultures containing nonadherent PBMCs. In contrast, both molecules significantly suppressed osteoclast formation in lymphocyte-depleted cultures. These data demonstrate that the cytokine milieu and/or state of cell activation determines how cells of the osteoclast precursor respond to IL-4 and IL-13.

Antineoplastic Agents↗

PubMed2002

Osteopontin posttranslational modifications, possibly phosphorylation, are required for in vitro bone resorption but not osteoclast adhesion.

Osteopontin (OPN), a phosphorylated bone matrix glycoprotein, is an Arg-Gly-Asp (RGD)-containing protein that interacts with integrins and promotes in vitro attachment of a number of cell types, including osteoclasts. Gene knockout experiments support the idea that OPN is important in osteoclastic activity. We hypothesize that posttranslational modifications (PTMs) of OPN can influence its physiological function. Previous studies have suggested that phosphorylation of OPN and bone sialoprotein (BSP) is necessary for promoting osteoclast adhesion. However, no reports have explored the importance of phosphoserines and other PTMs in OPN-promoted bone resorption. To study this question, we determined the activities of different forms of OPN and BSP in three in vitro assays: attachment of osteoclasts; formation of actin rings; and bone resorption. For each assay, cells were incubated for 4-24 h, in the presence or absence of RGDS or RGES peptides, to test the involvement of integrin binding. In addition to OPN, activities of milk OPN (fully phosphorylated) and recombinant OPN (rOPN, no phosphate) were compared. We purified two forms of OPN (OPN-2 and OPN-5), which differ in the level of phosphorylation, and compared their activities. For comparison, the activities of BSP and recombinant BSP (rBSP) were determined. All forms of OPN, including rOPN, significantly increased attachment of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. BSP and rBSP also promoted cell attachment. After 4 h of incubation, the proportion of cells with actin rings was increased with OPN, milk OPN, and BSP. In the presence of RGDS peptide, osteoclast retraction and the disruption of actin rings were observed, whereas no effect was seen with RGES. In the resorption assay, the number of pits and the total resorbed area per slice were increased in the presence of OPN, milk OPN, and BSP. As in other assays, the OPN enhancement of resorption was inhibited by RGDS, but not RGES, peptides. Significantly, rOPN and rBSP did not promote bone resorption. OPN-5 promoted resorption to a greater extent than OPN-2, and milk OPN significantly stimulated resorption to a greater extent than OPN. Our data suggest that: (1) the RGD sequence of OPN is essential in OPN-mediated cell attachment, actin ring formation, and bone resorption; and (2) some form of PTM, possibly phosphorylation, is necessary for in vitro osteoclastic bone resorption, but not for cell attachment and actin ring formation.

Actins↗

PubMed2002

Calcitonin induces dephosphorylation of Pyk2 and phosphorylation of focal adhesion kinase in osteoclasts.

Calcitonin induces the association and tyrosine phosphorylation of focal adhesion kinase (FAK), paxillin, and HEF1 in HEK-293 cells that overexpress the calcitonin receptor (C1a-HEK), but the hormone's effect on these adhesion-related proteins in osteoclasts is not known. We therefore studied the effect of calcitonin on the tyrosine phosphorylation and subcellular distribution of paxillin, HEF1, FAK, and Pyk2, a FAK-related tyrosine kinase, in osteoclasts. Osteoclasts expressed both Pyk2 and FAK, with Pyk2 much more highly expressed. The two tyrosine kinases and paxillin were prominently associated with small punctate structures that were most densely clustered in the region of the peripheral F-actin-rich ring. Some of the punctate structures stained either for Pyk2 alone or FAK alone. Treatment with calcitonin disrupted the actin ring and induced the loss of the peripheral staining of paxillin, Pyk2, and FAK. In calcitonin-treated osteoclast-like cells, the tyrosine phosphorylation of paxillin and FAK increased, whereas the tyrosine phosphorylation of Pyk2 decreased. Calcitonin also induced increased phosphorylation of Erk1 and Erk2 in osteoclasts, as it did in the C1a-HEK cells. The unexpected dephosphorylation of Pyk2 correlated with decreased phosphorylation of Tyr(402), the autophosphorylation site of Pyk2. The calcitonin-induced dephosphorylation of Pyk2 was not observed in C1a-HEK cells transfected with Pyk2, suggesting that the reduced phosphorylation seen in osteoclasts may be specific to these cells. Treatment of osteoclast-like cells with 12-phorbol 13-myristate acetate increased the tyrosine phosphorylation of both Pyk2 and FAK, and calphostin C, an inhibitor of protein kinase C, blocked calcitonin-stimulated FAK phosphorylation. Increasing intracellular calcium with ionomycin caused a decrease in the tyrosine phosphorylation of Pyk2 and the loss of the actin ring in a manner similar to the effect of calcitonin. Ionomycin had no effect on FAK tyrosine phosphorylation. Calcitonin (CT)-induced changes in Pyk2, FAK, and Erk1/2 phosphorylation were independent of c-Src.

Animals↗

PubMed2003

Inhibition of RANKL-induced osteoclast formation in mouse bone marrow cells by IL-12: involvement of IFN-gamma possibly induced from non-T cell population.

IL-12 was shown to have the potential to inhibit osteoclast formation in mouse bone marrow cells treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL). When bone marrow macrophages (BMM) were used as osteoclast precursors, IL-12 failed to inhibit M-CSF/RANKL-induced osteoclast formation from BMM. In coculture experiments using transwells, IL-12 did inhibit osteoclast formation from BMM cocultured with whole bone marrow cells. These results indicated that IL-12 indirectly affected M-CSF/RANKL-induced osteoclastogenesis in bone marrow cells and that the inhibition of IL-12 on osteoclast formation was caused by a humoral factor from bone marrow cells treated with IL-12. Experiments with anti-interferon (IFN)-gamma antibody and bone marrow cells from IFN-gamma receptor knockout mice revealed that IFN-gamma might be involved in the inhibition of osteoclast formation in this system. The expression of osteoprotegerin mRNA in bone marrow cells was not affected by treatment with IL-12. The inhibitory effect of IL-12 on osteoclast formation was also seen in the T cell-depleted bone marrow cells of normal mice and the whole bone marrow cells of athymic nude mice, while the inhibitory effect of IL-12 was partially suppressed in the B cell-depleted bone marrow cells. The inhibitory effect of IL-12 on M-CSF/RANKL-induced osteoclastogenesis was not accompanied with cell death, in contrast with our previous finding that the inhibitory effect of IL-12 on M-CSF/TNF-alpha-induced osteoclastogenesis is attributable to Fas and FasL-mediated apoptosis.

Acid Phosphatase↗

PubMed1997

Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry.

We have recently cloned cathepsin K from a human bone cDNA library. Since cathepsins are proposed to be involved in the degradation of mineralized bone matrix, we have investigated, by in situ hybridization and immunocytochemistry, the expression of the cathepsin K mRNA transcripts and protein in sections of bone and giant cell tumor to determine which cells express this enzyme. Within all tissues studied, cathepsin K was highly expressed in osteoclasts. Furthermore, the expression of cathepsin K mRNA in giant cell tumor tissue appeared to be confined to the periphery of the osteoclast indicating a compartmentalization of the mRNA. Immunohistochemistry confirmed the specific localization of cathepsin K to the osteoclast. In actively resorbing osteoclasts, the immunostaining was localized at the ruffled border, whereas in osteoclasts in sections of giant cell tumor, staining was observed in lysosomal vacuoles, which in some cases were seen to fuse with the cell membrane. Other cells within the bone, such as osteoblasts and osteocytes, did not express either the cathepsin K transcript or protein. However, there were very low levels of cathepsin K detected in a population of mononuclear cells, possibly representing osteoclast progenitor cells, within the marrow/stromal layer. The specific localization of cathepsin K within osteoclasts would therefore indicate the potential role of this enzyme in the bone resorptive process.

Blotting, Northern↗

PubMed1997

Detection of gelatinase B expression reveals osteoclastic bone resorption as a feature of early calvarial bone development.

Gelatinase B is a matrix metalloproteinase (MMP-9) produced by osteoclasts involved in bone resorption. Bone modeling, of which resorption is an integral part, is particularly evident in the intramembranous bones of the craniofacial region. To determine the role of osteoclasts in developing intramembranous bones we localized osteoclasts in calvariae from mice aged between embryonic day 16 and postnatal day 6, using gelatinase B and tartrate-resistant acid phosphatase activity (TRAP) as osteoclast markers. Through a combined approach of in situ hybridization and enzyme histochemistry, phenotypic differences between osteoclasts associated with calvarial bone were noted. Some cells expressed gelatinase B mRNA but were TRAP negative, whereas others demonstrated an overlap in enzyme profile exhibiting both TRAP activity and expressing gelatinase B mRNA. During more advanced development, most osteoclasts exhibited TRAP activity but did not express gelatinase B mRNA. The distribution of these cells differed, TRAP positive cells being detected in a widespread pattern at all ages, while gelatinase B transcripts were increasingly concentrated in areas of new and rapid bone growth, notably around the sutures. We propose the use of gelatinase B as an osteoclastic marker in the developing mouse. We conclude that gelatinase B may have a key role during early bone formation, the regulation of bone modeling, and perhaps in the maintenance of suture width.

Acid Phosphatase↗

PubMed1998

Localization of parathyroid hormone-related protein in osteoclasts by in situ hybridization and immunohistochemistry.

Using immunohistology with two specific antisera raised against N-terminal parathyroid hormone-related protein (PTHrP) and in situ hybridization (riboprobe to common coding exon), evidence is provided for the expression of PTHrP by mouse, rabbit, and human osteoclasts derived from several in vitro and in vivo sources. In cocultures of mouse bone marrow and calvarial cells treated with 1,25-dihydroxyvitamin D3, the generated osteoclasts expressed both PTHrP messenger RNA (mRNA) and protein. In addition, PTHrP was detected in the majority of actively resorbing osteoclasts in sections of newborn and adult mouse long bones. Using an in vivo intramembranous bone formation model in rabbits, expression of PTHrP mRNA and protein was demonstrated in osteoclasts at active bone resorption sites as well as in actively synthesizing osteoblasts and bone lining cells. Localization of PTHrP was also demonstrated in osteoclast-like cells of human giant cell tumors from bone. In some of these tumors, a small proportion of the multinucleated cells expressed tartrate resistant acid phosphatase (TRAP), but not PTHrP mRNA or protein. Finally, both mRNA and protein for PTHrP were expressed in osteoclasts in sections of bone or joints from patients with Paget's disease, rheumatoid arthritis, and osteoarthritis. These observations raise the possibility that PTHrP might participate in osteoclast function.

Animals↗

PubMed1998

Insulin receptor expression in primary and cultured osteoclast-like cells.

Skeletal growth is the net product of coordinated bone formation and resorption. Insulin is known to stimulate bone formation by actions on osteoblasts. It is not known whether insulin receptors are present on osteoclasts, or whether insulin regulates osteoclastic function. We present here immunocytochemical evidence of insulin receptor expression by mature mono- and multinucleated murine osteoclast-like cells generated in vitro, and in primary neonatal rat and mouse osteoclasts. Radiolabeled studies indicated that progressive enrichment of osteoclast-like cells in coculture was associated with increased insulin binding. When osteoclast-like cells generated in vitro were plated onto dentine slices, insulin dose-dependently inhibited pit formation by up to 80%, suggesting a role for insulin in osteoclast function. These data are consistent with an effect of insulin on bone resorption in addition to those previously recognized on bone formation, actions that together result in net bone growth.

Animals↗

PubMed1999

Conditioned medium of estrogen-treated osteoblasts inhibits osteoclast maturation and function in vitro.

The increase of bone resorption and reduction of bone mass in postmenopausal women can be prevented by treatment with estrogen. Although it is well established that estrogen treatment normalizes the increased bone turnover, the mechanism by which estrogen exerts its protective influence at the cellular and molecular level in bone remains elusive. It has been shown that osteoblasts are involved in osteoclast development and osteoclastic bone resorption. In this work we examine the effect of estrogen (E2) on osteoclast-mediated bone resorption via the medium conditioned by osteoblast cultures. The conditioned medium collected from osteoblast cultures without (CM) or with 0.1 nmol/L 17beta-estradiol (E-CM) was mixed in a 1:1 ratio with fresh osteoclast culture medium. Osteoclasts were isolated from the bone marrow of 3-day-old NMRI mice and cultured on bovine bone slices. The total number of multinucleated tartrate-resistant alkaline phosphatase (TRAP)-positive cells in cultures with CM and E-CM was similar to that of cells incubated in control medium. However, the number of osteoclasts containing more than three nuclei was significantly smaller in the cultures containing E-CM. The total area of resorption was only slightly decreased in cultures containing CM, but was markedly inhibited in cultures with E-CM. In osteoblast cultures, the production of interleukin (IL)-1 and IL-6, but not of TNF-alpha, was reduced by 0.1 nmol/L E2. Our data suggest that E2 treatment of osteoblasts decreases the production of factor(s) that induces osteoclast differentiation to multinucleated cells with a higher capacity for bone resorption.

Acid Phosphatase↗

PubMed2003

Cellular mechanisms of osteoclast formation and lacunar resorption in giant cell granuloma of the jaw.

BACKGROUND: Giant cell granuloma (GCG) is an osteolytic tumour of the jaw which is characterised by the presence of both mononuclear and multinucleated (osteoclast-like) giant cell components. The nature of these component cells and the pathogenesis of the extensive osteolysis associated with this lesion is uncertain. METHODS: Using cell culture techniques and immunohistochemistry, we defined the phenotypic characteristics of the mononuclear and multinucleated cells present in four cases of GCG of the jaw. We also analysed the cellular and humoral factors associated with osteoclast formation and osteolysis in these tumours and determined whether GCG stromal cells are capable of supporting osteoclast formation. RESULTS: GCG-derived giant cells expressed the phenotypic characteristics of osteoclasts (TRAP+, VNR+, and calcitonin responsive) and were capable of lacunar resorption. In addition to macrophages, the mononuclear cell population contained numerous spindle-shaped stromal cells which proliferated in culture and expressed RANKL; these GCG-stromal cells were capable of supporting human osteoclast formation from circulating monocyte precursors. CONCLUSION: Our findings indicate that the giant cells in GCG of the jaw are osteoclast-like and formed from monocyte/macrophage precursors which differentiate into osteoclasts under the influence of RANKL-expressing mononuclear stromal cells found in this lesion.

Acid Phosphatase↗

PubMed2002

Regulatory mechanisms of osteoblast and osteoclast differentiation.

Bone is continuously destroyed and reformed to maintain constant bone volume and calcium homeostasis in vertebrates throughout their lives. Osteoblasts and osteoclasts are specialized cells responsible for bone formation and resorption, respectively. Recent developments in bone cell biology have greatly changed our conceptions of the regulatory mechanisms of the differentiation of osteoblasts and osteoclasts. Bone morphogenetic proteins (BMPs) play critical roles in osteoblast differentiation. The discovery of Smad-mediated signals revealed the precise functions of BMPs in osteoblast differentiation. Transcription factors, Runx2 and Osterix, are found to be essential molecules for inducing osteoblast differentiation, as indicated by the fact that both Runx2-null mice and Osterix-null mice have neither bone tissue nor osteoblasts. Smad transcriptional factors are shown to interact with other transcription regulators, including Runx2. Also, the recent discovery of receptor activator of NF-kappaB ligand (RANKL)-RANK interaction confirms the well-known hypothesis that osteoblasts play an essential role in osteoclast differentiation. Osteoblasts express RANKL as a membrane-associated factor. Osteoclast precursors that express RANK, a receptor for RANKL, recognize RANKL through the cell-cell interaction and differentiate into osteoclasts. Recent studies have shown that lipopolysaccharide and inflammatory cytokines such as tumor necrosis factor receptor-alpha and interleukin I directly regulate osteoclast differentiation and function through a mechanism independent of the RANKL-RANK interaction. Transforming growth factor-beta super family members and interferon-gamma are also shown to be important regulators in osteoclastogenesis. These findings have opened new areas for exploring the molecular mechanisms of osteoblast and osteoclast differentiation.

Animals↗

PubMed2002

Macrophage colony-stimulating factor promotes the survival of osteoclast precursors by up-regulating Bcl-X(L).

Macrophage colony-stimulating factor (M-CSF) is known as one of the factors essential for osteoclast development. In the present study, we examined effects of M-CSF on the apoptotic pathway of osteoclast precursors and their underlying molecular mechanisms. Osteoclast precursors underwent apoptosis in the absence of M-CSF, even in the presence of receptor activator of NF-kappakB ligand (RANKL). Active caspase-3 and -9 were detected in the osteoclast precursors and treatments of precursors with their specific inhibitors (Z-DEVD-FMK and Z-LEHD-FMK) decreased the apoptosis. M-CSF decreased apoptosis in a dose-dependent manner with decreasing in active caspases-3 and -9 levels and up-regulating Bcl-X(L). Those effects of M-CSF on inhibiting apoptosis of osteoclasts precursor by regulating anti-apoptotic signals was more effective when combined with RANKL. These results demonstrate that M-CSF acts as a survival factor for the osteoclast precursors. Furthermore, it is believed that the apoptosis of osteoclast precursors may be involved in the activation of caspase-9 and that M-CSF may promote their survival through Bcl-X(L)-induced inhibition of caspase-9 activation.

Animals↗

PubMed2006

Tanshinone IIA inhibits osteoclast differentiation through down-regulation of c-Fos and NFATc1.

Bone is a dynamic tissue that is regulated by the activity of bone-resorbing osteoclasts and bone-forming osteoblasts. Excessive osteoclast formation causes diseases such as osteoporosis and rheumatoid arthritis. Natural substances may be useful as therapeutic drugs to prevent many diseases in humans because they avoid the many side effects of treatment with chemical compounds. Here we show that tanshinone IIA isolated from Salvia miltiorrhiza Bunge inhibits the receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclast differentiation of osteoclast precursors. Tanshinone IIA suppressed the expression levels of c-Fos and NFATc1 induced by RANKL. However, retrovirus-mediated overexpression of c-Fos induced the expression of NFATc1 despite the presence of tanshinone IIA and reversed the inhibitory effect of tanshinone IIA on osteoclast differentiation. Also, the introduction of osteoclast precursors with the NFATc1 retrovirus led to osteoclast differentiation in the presence of tanshinone IIA. Our results suggest that tanshinone IIA may have a role as a therapeutic drug in the treatment of bone disease such as osteoporosis.

Abietanes↗

PubMed1996

Phosphate transport in osteoclasts: a functional and immunochemical characterization.

Osteoclasts are polarized cells involved in bone resorption. They are exposed to high ambient concentrations of inorganic phosphate (Pi) during the active process of bone resorption. We hypothesize that osteoclasts may possess specific Pi-transport system(s) for transcellular movement of Pi released from bone into the resorption cavity. We have previously reported the existence of a Na-dependent Pi cotransporter in the avian osteoclast, which provides a model culture system for the fully differentiated phenotype capable of bone resorption. In whole cell Pi-uptake studies, the rate of Pi transport was sensitive to both ouabain and 2,4-DNP, an inhibitor of aerobic ATP production. When these osteoclasts were exposed to bone particles, there was an immediate stimulation of Pi transport, independent of de novo protein synthesis. The stimulatory effect of bone particles was inhibited by peptides with the Arg-Gly-Asp-Ser (RGDS) motif, an effect which implicates integrins and cell-matrix interaction in the regulation of Pi transport. We performed Western blots on both whole cell lysates and membrane fractions using a polyclonal antibody to the N-terminal of NaPi-2 (the rat variant) and found a single approximately 100 kDa protein; the non-immune serum was used as control. Immunofluorescence studies using the same N-terminal antibody to NaPi-2 detected the protein in discrete vesicles. There was an induction of the protein in membrane fractions isolated from osteoclasts cultured in the presence of bone particles. Our preliminary studies indicate that a Na-Pi cotransporter may exist in the avian osteoclast, immunologically related to the NaPi-2 family, and which may be regulated through integrin-mediated pathways in the presence of bone. We also hypothesize that there may be a redistribution of vesicular pools containing the Na-Pi cotransporter toward discrete plasma membrane sites on the polarized osteoclast for transcellular movement of Pi during active bone resorption.

Amino Acid Sequence↗

PubMed2006

Osteoclast-rich undifferentiated carcinomas of the urinary tract.

Osteoclast-like giant-cell neoplasms of the urinary tract are rare. They are composed of ovoid or spindle-shaped mononuclear cells with evenly spaced osteoclast-like giant cells. Terminology, histogenesis, and biologic behavior of these tumors remain controversial. Six cases of osteoclast-like giant-cell neoplasms of the urinary tract were identified from the consultation files of two of the authors. Patients were all male and elderly (range 65-82), with the exception of one 39-year-old male. In all, 3/6 tumors developed in the bladder and 3/6 in the renal pelvis. Size ranged from 5 to 11 cm. One bladder and three renal pelvis tumors were high stage (pT3) at time of presentation. Adjacent to the osteoclast-like giant-cell neoplasm in the same specimen, all patients had urothelial carcinoma in situ and/or high-grade papillary urothelial carcinoma. Multinucleated cells had identical morphological and immunohistochemical properties of osteoclasts; positive for CD-68, LCA, CD51 and CD54, and negative for cytokeratins and EMA. Varying percentages of mononuclear cells expressed alpha-smooth muscle actin (4/6), desmin (1/6), S-100 (4/6), LCA (2/6) and CD68 (6/6). However, mononuclear cells were also positive for epithelial markers in 4/6 tumors (cytokeratins AE-1/AE-3, Cam 5.2, CK7 and/or EMA). p53 stained mononuclear tumor cells in three cases, paralleling the staining on the accompanying urothelial carcinoma. Ki-67 stained mononuclear tumor cells, but not osteoclast-like giant cells. Follow-up data were available in five cases. One patient developed recurrence of noninvasive urothelial carcinoma and is still alive. Four patients were dead due to disease within 15 months, three with distant metastases. The intimate association of these tumors with urothelial carcinoma along with their immunohistochemical profile supports an epithelial origin for the mononuclear cells and non-neoplastic reactive histiocytic lineage for the osteoclast-like giant cells.

Adult↗

PubMed2003

Upregulation of osteoclast alpha2beta1 integrin compensates for lack of alphavbeta3 vitronectin receptor in Iraqi-Jewish-type Glanzmann thrombasthenia.

Osteoclasts utilize alphavbeta3 integrin adhesion to bone matrix during bone resorption. We have generated osteoclasts from the peripheral blood of Iraqi-Jewish patients with Glanzmann thrombasthenia (GT) who are completely deficient in beta3 integrin and exhibit a haemorrhagic diathesis resulting from the absence of platelet alphaIIbbeta3. We show that, in contrast to osteoclasts generated from normal subjects or patients with alphaIIb integrin deficiency, GT osteoclasts lack alphavbeta3. These osteoclasts exhibited a two- to fourfold increase in alpha2 and beta1 integrin expression, whereas other alphav integrins, including alphavbeta5, were not significantly affected. An accompanying decrease in bone resorption was observed, with 44% and 59% declines in pit number and depth, respectively, and resorption lacunae showed abnormal morphology on scanning electron microscopy. However, osteoclasts from GT developed in similar numbers to controls and exhibited an otherwise 'normal' phenotype. We conclude that the observed rise in alpha2beta1 expression compensates for the chronic genetic deficiency of alphavbeta3 in osteoclasts from patients with GT and is sufficient to enable bone resorption to proceed, albeit to a submaximal extent. This explains why Iraqi-Jewish patients with GT do not have osteopetrosis.

Adolescent↗

PubMed1994

Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase.

We have examined the effects of modulating nitric oxide (NO) levels on osteoclast-mediated bone resorption in vitro and the effects of nitric oxide synthase (NOS) inhibitors on bone mineral density in vivo. Diaphorase-based histochemical staining for NOS activity of bone sections or highly enriched osteoclast cultures suggested that osteoclasts exhibit substantial NOS activity that may account for basal NO production. Chicken osteoclasts were cultured for 36 hr on bovine bone slices in the presence or absence of the NO-generating agent sodium nitroprusside or the NOS inhibitors N-nitro-L-arginine methyl ester and aminoguanidine. Nitroprusside markedly decreased the number of bone pits and the average pit area in comparison with control cultures. On the other hand, NOS inhibition by N-nitro-L-arginine methyl ester or aminoguanidine dramatically increased the number of bone pits and the average resorption area per pit. In a model of osteoporosis, aminoguanidine potentiated the loss of bone mineral density in ovariectomized rats. Aminoguanidine also caused a loss of bone mineral density in the sham-operated rats. Inhibition of NOS activity in vitro and in vivo resulted in an apparent potentiation of osteoclast activity. These findings suggest that endogenous NO production in osteoclast cultures may regulate resorption activity. The modulation of NOS and NO levels by cells within the bone microenvironment may be a sensitive mechanism for local control of osteoclast bone resorption.

Amino Acid Oxidoreductases↗