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PubMed1988

Human serum alpha 2HS-glycoprotein modulates in vitro bone resorption.

We previously isolated a family of bone-resorbing proteins from human cancer ascites fluid and established that the three purified bone-resorbing proteins were chemically and immunochemically related to each other and to alpha-2HS glycoprotein (alpha 2HS). After this finding we purified the normal human serum counterpart of these ascites proteins and studied its effects on bone resorption. The bone-resorbing properties of normal human serum alpha 2HS were examined in vitro over a wide dose range. This normal human serum glycoprotein had a biphasic effect on 45Ca2+ release from bone. More specifically, this protein stimulated bone resorption at the lower concentrations tested, with a maximum effect [treated over control ratio of 2.5 +/- 0.30 (+/- SE); P less than 0.01] at 40 micrograms/mL. In contrast, at doses above 40 micrograms/mL, a sharp decline in calcium mobilization occurred, with a return to baseline occurring above 80 micrograms/mL. These results suggest that serum alpha 2HS may participate in the regulation of bone metabolism in vivo.

Adult↗

PubMed1991

Bradykinin synergistically potentiates interleukin-1 induced bone resorption and prostanoid biosynthesis in neonatal mouse calvarial bones.

Interleukin-1 (IL-1) alpha and beta dose-dependently stimulated the release of 45Ca and the formation of prostaglandin E2 (PGE2) and PGI2 in cultured mouse calvarial bones, with IL-1 beta being the most potent agonist. Bradykinin (BK; 10 nmol/l) synergistically potentiated the effect of IL-1 alpha (10 pg/ml) and IL-1 beta (5 pg/ml) both on 45Ca release and on biosynthesis of PGE2 and PGI2. The capacity of BK to potentiate IL-1 beta induced 45Ca release and PGE2 formation was seen at concentrations of BK from 1-1000 nmol/l. These data indicate that BK and IL-1, which are formed in inflammatory processes, may act in concert to stimulate bone resorption in the vicinity of inflammatory lesions.

Animals↗

PubMed1995

Evaluation of bone resorption: a common problem during impaired mobility.

Osteoporosis, the result of an imbalance between bone resorption and bone formation, is a potential problem for the individual with a spinal cord injury because of the immobility commonly associated with this impairment. This study was performed to determine the diagnostic value of a new assay for urinary Pyridinium crosslink (UPyr). Assays were performed on 62 first morning voided and 50 24-hour urine specimens from clients in a bone health clinic. Higher than normal levels of UPyr were observed in females with osteoporosis. UPyr correlated well with urinary hydroxyproline (r = 0.429, p = 0.005; conversely, there was an inverse relationship between bone density and UPyr (r = -0.489, p = 0.01), positive correlation (r = 0.43, p = 0.011) between the 24-hour UPyr and a serum marker of bone resorption. The study confirms that UPyr has the ability to identify states of high bone resorption. This assay should be a welcome addition to the bone health assessment of individuals with risk factors such as impaired physical mobility.

Adult↗

PubMed1994

Oral calcium suppresses biochemical markers of bone resorption in normal men.

Calcium supplementation decreases bone resorption and retards bone loss in women. There is little information about the effects of calcium supplementation in men. The effects of a 1-g oral calcium load at 0900 on bone-related biochemical variables were evaluated in 13 normal men (aged 51-70 y). Calcium administration was associated with increases in plasma ionized calcium (P < 0.001) and urinary calcium (P < 0.001), and a decrease in plasma parathyroid hormone (P < 0.001). There was a nonsignificant trend (r = -0.47, P = 0.11) for the decrease in plasma parathyroid hormone to be related to radiocalcium absorption. After the calcium load there were decreases in the urinary hydroxyproline-creatinine ratio from 11 +/- 1.1 to 7.9 +/- 0.6 (P < 0.01), the urinary deoxypyridinoline-creatinine ratio from 14.0 +/- 1.8 to 10.1 +/- 0.9 (P < 0.05), and the urinary pyridinoline-creatinine ratio from 52 +/- 5 to 40 +/- 3 (P < 0.01) between baseline and 6 h. There was no change in plasma osteocalcin. These observations indicate that a 1-g calcium load suppresses biochemical markers of bone resorption for > or = 6 h in normal men and support the concept that calcium supplementation may be useful in the prevention of bone loss in men.

Absorption↗

PubMed2004

Recent advances in osteoclast biology and pathological bone resorption.

The osteoclast is a bone-degrading polykaryon. Recent studies have clarified the differentiation of this cell and the biochemical mechanisms it uses to resorb bone. The osteoclast derives from a monocyte/macrophage precursor. Osteoclast formation requires permissive concentrations of M-CSF and is driven by contact with mesenchymal cells in bone that bear the TNF-family ligand RANKL. Osteoclast precursors express RANK, and the interaction between RANKL and RANK (which is inhibited by OPG) is the major determinant of osteoclast formation. Hormones, such as PTH/PTHrP, glucocorticoids and 1,25(OH)2D3, and humoral factors, including TNFalpha, interleukin-1, TGFss and prostaglandins, influence osteoclast formation by altering expression of these molecular factors. TNFalpha, IL-6 and IL-11 have also been shown to promote osteoclast formation by RANKL-independent processes. RANKL-dependent/independent osteoclast formation is likely to play an important role in conditions where there is pathological bone resorption such as inflammatory arthritis and malignant bone resorption. Osteoclast functional defects cause sclerotic bone disorders, many of which have recently been identified as specific genetic defects. Osteoclasts express specialized proteins including a vacuolar-type H+-ATPase that drives HCl secretion for dissolution of bone mineral. One v-ATPase component, the 116 kD V0 subunit, has several isoforms. Only one isoform, TCIRG1, is up-regulated in osteoclasts. Defects in TCIRG1 are common causes of osteopetrosis. HCl secretion is dependent on chloride channels; a chloride channel homologue, CLCN7, is another common defect in osteopetrosis. Humans who are deficient in carbonic anhydrase II or who have defects in phagocytosis also have variable defects in bone remodelling. Organic bone matrix is degraded by thiol proteinases, principally cathepsin K, and abnormalities in cathepsin K cause another sclerotic bone disorder, pycnodysostosis. Thus, bone turnover in normal subjects depends on relative expression of key cytokines, and defects in osteoclastic turnover usually reflect defects in specific ion transporters or enzymes that play essential roles in bone degradation.

Animals↗

PubMed1994

Direct effect of calcium channel antagonists on osteoclast function: alterations in bone resorption and intracellular calcium concentrations.

Osteoclasts attach to mineralized surfaces and resorb bone matrix, releasing calcium into the area surrounding the osteoclast. The production of high levels of extracellular calcium increases intracellular calcium concentrations ([Ca2+]i), and bone resorption is decreased. To study this mechanism, the dihydropyridine-sensitive L-type calcium channel antagonists PN 200-110, (-)202-791, and nifedipine were studied for their effects on bone resorption using the disaggregated osteoclast pit assay. Changes in [Ca2+]i after treatment with these compounds were determined with the fluoroprobe fura2. In osteoclast-enriched cultures, significant decreases in bone resorption were noted in the presence of PN 200-110 and (-)202-791. The decrease in bone resorption correlated with an increase in [Ca2+]i. To determine whether the effects of these compounds on osteoclasts were mediated via osteoblasts, proliferation and differentiation of rat osteoblast-like cells (ROS 17/2.8) were examined after the addition of these agents. There were no changes in osteoblast proliferation or differentiation, as determined by [3H]thymidine incorporation and specific activity of alkaline phosphatase, after treatment with these compounds at concentrations that inhibited bone resorption in the disaggregated pit assay. This lack of effect of calcium channel antagonists on osteoblast growth and differentiation at concentrations used to inhibit osteoclast function suggests that the effects of PN 200-110 and (-)202-791 on the osteoclast are not mediated via the osteoblast. In addition, conditioned medium recovered from ROS 17/2.8 cultures treated with PN 200-110 or (-)202-791 had no effect on pit formation compared to the conditioned medium from cell-free cultures. This lack of effect of calcium channel conditioned medium on bone resorption provides additional evidence that PN 200-110 and (-)202-791 are decreasing bone resorption directly by altering osteoclast function, not through osteoblast-osteoclast interactions. The addition of (-)202-791 or PN 200-110 to osteoclasts resulted in a dose-dependent rise in [Ca2+]i. These data suggest that calcium channel antagonists may bind to the calcium channel of the osteoclast and lock it in an open state, leading to increased [Ca2+]i and decreased bone resorption.

Animals↗

PubMed2002

[The drug treatment for bone resorption in the oral area].

The bone resorption in the oral area can be divided into the inflammatory and the metabolic bone resorption. In this review, we show a possibility for drug treatment in oral area, focusing on the drug development of TNF antagonist which inhibits the actions of both TNF-alpha and RANKL; the cytokines which have a critical role in the inflammatory bone resorption.

English Abstract↗

PubMed1992

Evidence for an autocrine/paracrine role for interleukin-6 in bone resorption by giant cells from giant cell tumors of bone.

Interleukin-6 (IL-6) is a multifunctional cytokine whose role in osteoclastic bone resorption has not been clearly defined. Therefore, we have used giant cells, which express many features of osteoclasts, from giant cell tumors of bone as a model to examine the role that IL-6 may play in human osteoclastic bone resorption. We found that conditioned medium from 24-h cultures of highly purified giant cells (10(6)/ml) contained large amounts of IL-6 (37.9 +/- 8.8 ng/ml), similar to the amount of IL-6 produced by tumor stromal cells (29.8 +/- 11.5 ng/ml). Giant cells and stromal cells from giant cell tumors expressed IL-6 mRNA, as indicated by polymerase chain reaction analysis and in situ hybridization studies, and immunohistochemical techniques demonstrated that the giant cells expressed IL-6 receptors. The addition of a neutralizing antibody to IL-6 significantly decreased the area of dentine resorbed by purified giant cells in a dose-dependent manner, and the addition of IL-6 to cultures of purified giant cells pretreated with anti-IL-6 restored the resorbing capacity of the giant cells. These data suggest that IL-6 may act as both an autocrine and a paracrine factor for human osteoclasts and play an important role in the bone-resorbing capacity of these cells.

Base Sequence↗

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↗

PubMed1989

Persistence of increased bone resorption and possible role of dehydroepiandrosterone as a bone metabolism determinant in osteoporotic women in late post-menopause.

Specific data on bone metabolism in the late post-menopause are relatively scarce. This study presents data on the biochemical, hormonal and bone mineral status of a selected group of 22 osteoporotic women with at least 1 vertebral fracture who had been post-menopausal for a minimum of 5 yr. Bone resorption parameters were elevated in over two-thirds of these patients. The serum levels of dehydroepiandrosterone and its sulphate were negatively correlated with age and years since menopause but positively correlated with bone mineral content, bone turnover parameters (urinary calcium/creatinine, osteocalcin), 1,25-dihydroxy-vitamin D levels and the 1,25-dihydroxy-vitamin D/25-hydroxy-vitamin D ratio. These findings indicate that careful evaluation of the bone turnover rate in the late post-menopause can still have an important bearing on therapeutic decisions. They also support the theory that adrenal androgens play a role in bone mineral metabolism in the late post-menopause.

Age Factors↗

PubMed2003

Contribution of membrane-associated prostaglandin E2 synthase to bone resorption.

This study initially confirmed that, among prostaglandins (PGs) produced in bone, only PGE(2) has the potency to stimulate osteoclastogenesis and bone resorption in the mouse coculture system of osteoblasts and bone marrow cells. For the PGE(2) biosynthesis two isoforms of the terminal and specific enzymes, membrane-associated PGE(2) synthase (mPGES) and cytosolic PGES (cPGES) have recently been identified. In cultured mouse primary osteoblasts, both mPGES and cyclooxygenase-2 were induced by the bone resorptive cytokines interleukin-1, tumor necrosis factor-alpha, and fibroblast growth factor-2. Induction of mPGES was also seen in the mouse long bone and bone marrow in vivo by intraperitoneal injection of lipopolysaccharide. In contrast, cPGES was expressed constitutively both in vitro and in vivo without being affected by these stimuli. An antisense oligonucleotide blocking mPGES expression inhibited not only PGE(2) production, but also osteoclastogenesis and bone resorption stimulated by the cytokines, which was reversed by addition of exogenous PGE(2). We therefore conclude that mPGES, which is induced by and mediates the effects of bone resorptive stimuli, may make a target molecule for the treatment of bone resorptive disorders.

Animals↗

PubMedDate not supplied

Comparison of serum bone resorption markers in the diagnosis of skeletal metastasis.

BACKGROUND: There are several bone resorption markers which are generated by different mechanisms. The serum level of 3 different bone resorption markers in cancer patients with or without skeletal metastasis was compared to see whether the markers exhibit clinically significant differences useful for metastatic screening. PATIENTS AND METHODS: Serum bone metabolic markers were measured in 75 cancer patients with and 201 cancer patients without skeletal metastasis. The 3 bone resorption markers, N-terminal cross-linked telopeptide of type I collagen (NTx), pyridinoline cross-linked carboxy-terminal telopeptides of type I collagen (ICTP) and tartrate-resistant acid phosphatase type 5b (TRAP 5b), and two bone formation markers, procollagen type I C-terminal peptide (PICP) and procollagen type I N-terminal peptide (PINP), were measured in the single sample. Each marker serum level was compared with the menopausal and the osseeous metastatic status assessed using Soloway's method for each patient. RESULTS: Bone resorption marker serum levels, except for ICTP, were about 16% larger in postmenopausal patients than in premenopausal patients. All 3 bone resorption marker serum levels were 3-4 times greater in patients with extensive skeletal metastasis (extent of disease III; EOD = III) than in patients with no osseous metastasis. Although ROC analysis indicated each bone resorption marker had a similar sensitivity and specificity regarding the ability to detect osseous metastasis, some differences were detectable. The T-score of TRAP 5b was elevated, but not significantly so, in patients with a small bone metastatic burden (EOD = I). In contrast, although the T-score of NTx was not elevated in patients with a small metastatic burden (EOD = I), it was significantly elevated in patients with extensive osseous metastasis (EOD = III). CONCLUSION: Three bone resorption markers with different generation mechanisms showed a difference in menopause and osseous metastasis status. The level of ICTP was not elevated in postmenopausal patients, but the levels of NTx and TRAP 5b. In osseous metastasis, even though not statistically significant, TRAP 5b increased in patients with a small bone metastatic burden and NTx increased in patients with extensive bone metastatic burden.

Acid Phosphatase↗

PubMed1992

Osteoclastic superoxide generation: taking control of bone resorption using modulators of superoxide concentrations.

We have examined the role of superoxide in bone resorption by stimulating defective superoxide production and bone resorption in patients with osteopetrosis and inhibiting superoxide production and bone resorption in murine calvarial explants. Interferon gamma treatment did stimulate superoxide generation and bone resorption in patients with osteopetrosis as evidenced by a reduction in bone volume and an increase in biochemical markers of bone resorption. Further, lowering the superoxide concentrations within calvarial osteoclasts using a scavenger, desferal manganese, decreased bone resorption. We conclude that superoxide generation by osteoclasts is necessary for normal osteoclastic function.

Animals↗

PubMed2006

Expression of mouse osteoclast K-Cl Co-transporter-1 and its role during bone resorption.

UNLABELLED: To assess the role of Cl- transport during osteoclastic bone resorption, we studied the expression and function of K+/Cl- co-transporters (KCCs). KCC1 and chloride channel-7 were found to be expressed in mouse osteoclasts. The KCC inhibitor, R(+)-butylindazone (DIOA), KCC1 antisense oligo-nucleotides, and siRNA suppressed osteoclastic pit formation. DIOA also decreased Cl- extrusion and reduced H+ extrusion activity. These results show that KCC1 provides a Cl- extrusion mechanism accompanying the H+ extrusion during bone resorption. INTRODUCTION: Mice with deficient chloride (Cl-) channels, ClC7, show severe osteopetrosis, resulting from impairment of Cl- extrusion during osteoclastic bone resorption. However, the expression and functional role of Cl- transporters other than ClC7 in mammalian osteoclasts is unknown. The aim of this study was to determine expression of K+/Cl- co-transporters (KCCs) and their functional role for bone resorption in mouse osteoclasts. MATERIALS AND METHODS: Mouse osteoclasts were derived from cultured bone marrow cells with macrophage-colony stimulating factor (M-CSF) and RANKL or from co-culture of bone marrow cells and primary osteoblasts. We examined the expression of Cl- transporters using RT-PCR, immunochemical, and Western blot methods. The effects of Cl- transport inhibitors on H+ and Cl- extrusion were assessed by measuring intracellular H+ ([H+]i) and Cl- ([Cl-]i). The effects of inhibitors, antisense oligo-nucleotides, and siRNA for Cl- transporters on bone resorption activities were evaluated using a pit formation assay. RESULTS AND CONCLUSIONS: Mouse osteoclasts express not only ClC7 but also K+/Cl- co-transporter mRNA. The existence of KCC1 in the cell membrane of mouse osteoclasts was confirmed by immunochemical staining and Western blot analysis. KCC inhibitors and Cl- channels blockers increased [Cl-]i and [H+]i in resorbing osteoclasts, suggesting that the suppression of Cl- extrusion through KCC and Cl- channels leads to reduced H+ extrusion activity. The combination of both inhibitors greatly suppressed these extrusion activities. KCC inhibitors and Cl- channel blockers also decreased osteoclastic bone resorption in our pit area essay. Furthermore, KCC1 antisense oligo-nucleotides and siRNA suppressed osteoclastic pit formation as well as treatment of ClC7 inhibitors. These results indicate that K+/Cl- co-transporter-1 expressed in mouse osteoclasts acts as a Cl- extruder and plays an important role for H+ extrusion during bone resorption.

Animals↗

PubMed1988

Inhibition of in vitro bone resorption by a parathyroid hormone receptor antagonist in the canine adenocarcinoma model of humoral hypercalcemia of malignancy.

In vitro bone resorption induced by tumor extract derived from a hypercalcemic canine adenocarcinoma was significantly inhibited by the PTH receptor antagonist, [Nle8,18,Tyr34]bovine (b) PTH-(3-34) amide. Dose-response curves were prepared for in vitro bone resorption induced in neonatal mouse calvaria by tumor extract, bPTH-(1-34), and prostaglandin E2. A 1:2000-fold ratio of bPTH-(1-34) to [Nle8,18,Tyr34]bPTH-(3-34) amide significantly inhibited bone resorption induced by bPTH-(1-34); however, a 1:10,000 ratio completely antagonized bone resorption. At equivalent potency (1.80-fold stimulation of in vitro bone resorption) of tumor extract compared to bPTH-(1-34), [Nle8,18,Tyr34]bPTH-(3-34) amide (5.0 microM) was capable of significantly reducing in vitro bone resorption. Bone resorption induced by tumor extract (1.35-fold stimulation) was inhibited by [Nle8,18,Tyr34]bPTH-(3-34) amide at concentrations of 5.0 and 1.0 microM. Bone resorption induced by prostaglandin E2 (300 nM) was not inhibited by [Nle8,18,Tyr34]bPTH-(3-34) amide (5.0 microM). These data indicate that [Nle8,18,Tyr34]bPTH-(3-34) amide antagonizes in vitro bone resorption induced by bPTH-(1-34) in a dose-dependent manner and significantly inhibits bone resorption induced by the canine adenocarcinoma model of humoral hypercalcemia of malignancy.

Adenocarcinoma↗

PubMed1989

Some factors connected with alveolar bone resorption.

In this study correlations are described between alveolar bone resorption, patient's age, duration of edentulousness, the number of dentures which have been worn, and dentures being worn day and night. The sample of patients for this study consisted of 92 edentulous persons treated with complete dentures at a dental school clinic. The test subjects were asked to fill in a questionnaire to obtain data regarding the research factors. A method for the classification of alveolar bone resorption was developed and the test subjects were divided into classes for alveolar bone resorption according to this method. All data were processed by means of a computer program. The longer the test subjects had been edentulous and the more dentures they had worn, the more intensive was the alveolar bone resorption, particularly in the lower jaw. No significant correlation was found between alveolar bone resorption and dentures being worn day and night.

Adult↗

PubMedDate not supplied

Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer.

We studied bone biopsies from 65 normocalcaemic women with breast cancer and predominantly osteolytic bone metastases in order to examine the pathophysiology of bone destruction in metastatic bone disease. Quantitative histomorphometric measurements were made at sites of tumour involvement, at sites adjacent to tumour tissue and at sites distant from tumour tissue. There were no significant differences in bone volume or in indices of bone resorption or formation between biopsies taken from sites distant from tumour and the controls. Bone resorption, as judged by eroded surface, increased progressively from bone distant from tumour to tumour-laden bone. The number of osteoclasts was significantly increased in bone immediately adjacent to tumour and within metastases. There was no decrease in the ratio of osteoclast to eroded surface in breast cancer compared to controls suggesting that increased resorption in breast cancer was mainly osteoclast mediated and locally activated by the tumour. Two thirds of the biopsies taken from tumour involved regions showed osteosclerosis with woven bone formation. The volume of the pre-existing lamellar trabecular bone was lower than normal in 75% of these biopsies, suggesting that bone resorption must have been increased before the onset of woven bone formation. Since all patients were receiving hormonal treatment or chemotherapy, it is likely that osteosclerosis at sites of previous resorption mainly resulted from the basic cancer treatment as a sign of response to treatment. Osteoclastic bone resorption was, however, not completely inhibited by the active cancer treatment.

Adult↗

PubMed1984

Effect of substrate composition on bone resorption by rabbit osteoclasts.

Slices of human femoral cortical bone were prepared with a carborundum wheel. Osteoclasts were isolated from neonatal rabbit long bones and incubated on either untreated, demineralized or anorganic preparations of these bone slices. Anorganic bone showed extensive tracts of uninterrupted surface excavation after incubation, while untreated bone tended to show discontinuous excavations of smaller total volume; demineralized bone was not resorbed. The endosteal surface of adult rat calvaria was also used as a substrate for osteoclastic bone resorption. The endosteal surface was exposed and rendered acellular, and was used either without further treatment or after incubation in collagenase. Bone resorption occurred only in those calvaria pre-treated with collagenase. These experiments imply that osteoclastic contact with bone mineral rather than the endosteal surface is the stimulus that initiates bone-resorptive behaviour in osteoclasts. The mechanism by which osteoblasts induce osteoclastic bone resorption may be through the known ability of osteoblasts to secrete collagenase, which, by digestion of the unmineralized lamina limitans of endosteal surfaces, exposes bone mineral to osteoclastic contact.

Animals↗