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PubMed2006

Estradiol inhibits adhesion and promotes apoptosis in murine osteoclasts in vitro.

Osteoporosis caused by estrogen deficiency is characterized by enhanced bone resorption mediated by osteoclasts. Adhesion to bone matrix and survival of differentiated osteoclasts is necessary to resorb bone. The aim of our study was to investigate the in vitro effects of estradiol on murine osteoclasts. RAW 264.7 cells treated with 30 ng/ml RANK-L were used as a model for osteoclastogenesis. Estradiol (10(-8)M) for 5 days induced an inhibition of osteoclast differentiation and beta3 expression. Estradiol inhibited significantly the adhesion of mature osteoclasts by 30%. Furthermore estradiol-induced apoptosis shown by with nuclear condensation and Bax/Bcl2 ratio. In addition, estradiol enhanced caspase-3, -8 and -9 activities. This effect completely disappeared using specific caspase-8 inhibitor. However, increased caspase-3 activity by estradiol was observed in the presence of caspase-9 inhibitor, indicating the preferential involvement of caspase-8 pathway. Fas and FasL mRNA expression was not regulated by estradiol. However, estradiol enhanced caspase-3 activity in Fas-induced apoptosis on mature osteoclasts, suggesting that this might interact with the Fas-signaling pathway. These data suggest that estradiol decreases bone resorption by several mechanisms including adhesion and apoptosis of osteoclasts.

Animals↗

PubMed2005

Bone resorption by aryl hydrocarbon receptor-expressing osteoclasts is not disturbed by TCDD in short-term cultures.

Polychlorinated dibenzo-p-dioxins (PCDDs) are highly toxic environmental contaminants, and 2,3,7,8-tetrachlorobenzo-p-dioxin (TCDD) is the most potent dioxin. Dioxins bind specifically to the cytosolic aryl hydrocarbon receptor (AHR), which is a ligand-activated transcription factor, and a majority of toxic effects of dioxins are mediated via AHR. We have recently demonstrated that TCDD disrupts bone modeling and decreases bone mechanical strength, and that partial resistance to these effects is related to an altered transactivation domain in AHR structure. In order to better understand the effects of dioxins on bone, we studied the presence and precise localization of AHR and also the number and activity of osteoclasts after TCDD treatments. Total RNA was extracted from mixed bone cell population cultures and expression of AHR mRNA was studied using RT-PCR. Bone cells expressed a considerable amount of AHR mRNA. To see which bone cells express AHR, immunostainings were performed in primary rat bone cell cultures, pure human osteoclast cultures and histological sections from AHR knockout and wild type bones. Immunostaining revealed a strong expression of AHR both in osteoclasts and osteoblasts with an especially prominent stain in bone resorbing osteoclasts. Effects of dioxin on primary bone cells were evaluated after TCDD treatment in the pit formation assay. The activity of osteoclasts was not affected measured as the percentage of active osteoclasts and the actual area of resorbed bone. These data indicate that even though TCDD-treated bones show decreased mechanical strength and size, this is not a direct result from increased osteoclastic bone resorption.

Animals↗

PubMed2005

Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo.

Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts. To investigate the effect of the T253I mutation in LRP5 on osteoclasts, we isolated CD14+ monocytes from ADOI patients and assessed their ability to generate osteoclasts when treated with RANKL and M-CSF compared to that of age- and sex-matched control osteoclasts. We found normal osteoclastogenesis, expression of osteoclast markers, morphology, and localization of proteins involved in bone resorption, such as ClC-7 and cathepsin K. The ability to resorb bone was also normal. In vivo, we compared the bone resorption and bone formation response to T3 in ADOI patients and age- and sex-matched controls. We found attenuated resorptive response to T3 stimulation, despite a normal bone formation response, in alignment with the reduced number of osteoclasts in vivo. These data demonstrate that ADOI osteoclasts are normal with respect to all aspects investigated in vitro. We speculate that the mutations causing ADOI alter the osteoblastic phenotype toward a smaller potential for supporting osteoclastogenesis.

Adult↗

PubMed1999

Inhibition of experimental bone resorption and osteoclast formation and survival by 2-aminoethanesulphonic acid.

It is known that bone resorption is mediated by osteoclasts, and lipopolysaccharide (LPS) and inflammatory mediators such as interleukin-1 (IL-1) and prostaglandin E2 (PGE2) induce osteoclast differentiation from haemopoietic cells, 2-aminoethanesulphonic acid, which is known as taurine, is an important nutrient and is added to most synthetic human infant milk formulas. In this study, it was found that 2-aminoethanesulphonic acid inhibits the stimulation of bone resorption mediated by LPS of the periodontopathic microorganism Actinobacillus actinomycetemcomitans Y4 in organ cultures of newborn mouse calvaria. The effect of 2-aminoethanesulphonic acid on the development and survival of osteoclast-like multinucleated cells produced in a mouse bone-marrow culture system was also examined. 2-aminoethanesulphonic acid (100 microg/ml) suppressed the formation of these osteoclast-like cells in the presence of LPS of A. actinomycetemcomitans Y4, IL-1alpha or PGE2 in mouse marrow cultures. On the other hand, 2-aminoethanesulphonic acid did not inhibit 1alpha, 25-dihydroxyvitamin D3-mediated osteoclast differentiation. Although IL-1alpha elongated the survival of the osteoclast-like cells, 2-aminoethanesulphonic acid blocked the supportive effect of IL-1alpha on osteoclast survival. 2-aminoethanesulphonic acid showed no effect on the growth of mouse osteoblasts. Finally, it was found that 2-aminoethanesulphonic acid inhibited alveolar bone resorption in experimental periodontitis in hamsters. These results suggest that 2-aminoethanesulphonic acid is an effective agent in preventing inflammatory bone resorption in periodontal diseases.

Aggregatibacter actinomycetemcomitans↗

PubMed1999

Inhibitory effect of genistein on osteoclast-like cell formation in mouse marrow cultures.

The effect of genistein on osteoclast-like cell formation in mouse marrow culture in vitro was investigated. The bone marrow cells were cultured for 7 days in alpha-minimal essential medium containing a well-known bone resorbing agent [parathyroid hormone (1-34) (PTH), prostaglandin E2 (PGE2), 1,25 dihydroxyvitamin D3 (VD3), or lipopolysaccharide (LPS)] with an effective concentration. Osteoclast-like cell formation was estimated by staining for tartrate-resistant acid phosphatase (TRACP), a marker enzyme of osteoclasts. The presence of PTH (10(-8) M), PGE2 (10(-6) M), VD3 (10(-8) M), or LPS (1 microg/mL) induced a remarkable increase in osteoclast-like multinucleated cells. These increases were inhibited significantly in the presence of genistein (10(-7) to 10(-5) M). The inhibitory effect of genistein (10(-5) M) was equal to that of 17 beta-estradiol (10(-8) M), calcitonin (10(-9) M), or zinc sulfate (10(-5) M). Genistein (10(-5) M) significantly inhibited dibutyryl cyclic adenosine monophosphate (10(-5) M)-induced osteoclast-like cell formation. However, genistein (10(-5) M) did not inhibit phorbol 12-myristate 13-acetate-induced osteoclast-like cell formation. The present study demonstrated that genistein has a potent inhibitory effect on osteoclast-like cell formation in mouse marrow culture. The inhibitory action of genistein may involve in cyclic AMP signaling.

Animals↗

PubMed2003

A hybrid peptide derived from cecropin-A and magainin-2 inhibits osteoclast differentiation.

The adult skeleton is in a dynamic state, being continually broken down and reformed by the coordinated actions of osteoclasts and osteoblasts. Increased osteoclast activity may contribute to the development of osteoporosis. Therefore, the intervention of osteoclast-mediated bone resorption is considered as an effective therapeutic approach in the treatment of osteoporosis. In the course of searching for agents that inhibit osteoclast differentiation and activation, we found that a novel hybrid peptide P1 derived from cecropin-A and magainin-2 reduced osteoclast differentiation in various osteoclast culture systems. As this peptide had no cytotoxicity on various cultures of primary cells and established cell lines, its inhibitory effect on osteoclastogenesis was not due to general cytotoxicity. The effects of P1 on osteoclasts appear to be mediated through the inhibition of NF-kappaB and JNK activation induced by the osteoclastogenic cytokine, receptor activator of NF-kappaB ligand (RANKL). These results provide an evidence for the potential usefulness of P1 for the treatment of bone-resorbing diseases.

Animals↗

PubMed2002

A feline assay using osteoclasts generated in vitro from peripheral blood for screening anti-resorptive agents.

Musculo-skeletal diseases are a major cause of pain and suffering in cats and several conditions involve increased bone resorption by osteoclasts. However, little is known about the biology of these cells in the cat. In this study we established a method to generate feline osteoclasts from blood mononuclear cells stimulated by macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL). Cultured osteoclasts are multinucleated, express tartrate resistant acid phosphatase (TRAP), form F-actin rings and resorb bone. They express alpha(v)beta3 vitronectin receptor and osteoclast enzymes, cathepsin K and MMP9; the myeloid antigen, CD18, and the megakaryocyte/platelet integrin, CD41, are absent. This phenotype is typical of osteoclasts from other species. Three resorption inhibitors were examined for activity against feline osteoclasts. Calcitonin, bisphosphonate and RGD integrin inhibitory peptide all reduced bone resorption at doses similar to those efficacious in rabbit or human. We conclude that blood-derived osteoclast cultures are a suitable in vitro system for assessing the ability of drugs to inhibit bone resorption in domestic cats.

Acid Phosphatase↗

PubMed2003

The reaction of osteoclasts when releasing osteocytes from osteocytic lacunae in the bone during bone modeling.

Osteocytes are released from the osteocytic lacunae when osteoclasts resorb the bone matrix during bone modeling and remodeling. It remains unknown how osteoclasts react when releasing osteocytes during bone modeling, and the fate of these released osteocytes is also unclear. Femoral mid-shafts of 2-day-old kittens were sectioned into serial 0.5 microm-thick semithin or 0.1 microm-thick ultrathin sections, and examined by light microscopy (LM) and transmission electron microscopy (TEM). The sections showed many osteoclasts at the endosteum but there were no osteoblasts. There were many half-released, fully released, half-exposed, and fully exposed osteocytes on the bone surfaces. Many cell-like structures were seen in the cell bodies of osteoclasts by LM, and some semithin sections were re-sectioned into ultrathin sections for re-observation by TEM. By TEM, these were determinated to be mononuclear cells. The serial ultrathin sections showed that the mononuclear cells appeared to be engulfed in osteoclasts on one section but that the cell was connected with the bone surface of the osteocytic lacuna on another section. These results show that the mononuclear cells in the osteoclasts were osteocytes. The present study suggests that osteoclasts engulf some osteocytes but do not engulf others when releasing osteocytes during bone modeling.

Animals↗

PubMed2003

Effects of beta-adrenergic agonists on bone-resorbing activity in human osteoclast-like cells.

In the present study, we demonstrate for the first time that beta-adrenergic agonists stimulate bone-resorbing activity in human osteoclast-like multinucleated cells (MNCs). Osteoclast-like MNCs constitutively expressed mRNA for alpha1B-, alpha2B- and beta2-adrenergic receptor (AR) in addition to characteristic markers of mature osteoclast, such as calcitonin receptor (CT-R), tartrate-resistant acid phosphatase (TRAP), alphaV-chain of integrin (Int alphaV), carbonic anhydrase II (CA-II) and cathepsin K (Cathe K). Epinephrine (1 microM; alpha,beta-adrenergic agonist) up-regulated expression of Int alphaV, CA-II and Cathe K in the osteoclast-like MNCs. Osteoclastic resorbing activity was markedly increased by isoprenaline (1 microM; beta-adrenergic agonist), moderately by epinephrine, but poorly by phenylephrine (1 microM; alpha1-adrenergic agonist). The actin ring, which was suggested to be correlated with bone-resorbing activity, was clearly observed in osteoclast-like MNCs treated with isoprenaline and epinephrine, but faintly in those treated with phenylephrine. These findings suggest that beta-adrenergic agonists directly stimulate bone-resorbing activity in matured osteoclasts.

Adrenergic beta-Agonists↗

PubMed1994

Osteoclast recruiting activity in bone matrix.

An activity that recruits osteoclasts has been identified and partially characterized from bone matrix. Bone-derived osteoclast recruiting activity (BORA) was co-purified with osteogenin, a bone inductive protein. Osteogenin was extracted from bovine bone with 6 M urea and purified by chromatography on hydroxyapatite, heparin-Sepharose and Sephacryl S-200 gel filtration. The biologically active osteoclast formation-stimulating material was further purified by C18 reverse phase HPLC. BORA is obviously distinct from osteogenin and transforming growth factor beta (TGF-beta), since further purified osteogenin and pure TGF-beta did not stimulate the formation of osteoclast-like cells. BORA (0.1-10 micrograms/ml) stimulated the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNC) in a dose-dependent manner. These multinucleated cells resorbed bone when cultured on bovine bone slices. The effect of BORA is primarily directed to differentiate osteoclast precursors, since it did not stimulate osteoclast function in in vitro resorption assay where disaggregated rat osteoclasts were cultured on bovine bone slices. However, after 24 h preincubation with 50 nM PTH in the mouse calvaria assay, BORA at 10 micrograms/ml significantly stimulated bone resorption.

Animals↗

PubMed1999

Rac-GTPase, osteoclast cytoskeleton and bone resorption.

The members of the Rho-GTPase subfamily, Rac1 and Rac2, are intimately involved in the organization of the cytoskeleton, and the p21-activated kinases or PAKs are targets of these proteins. Rac1 and Rac2 are also essential components of NADPH oxidase, the enzyme responsible for generating free radicals. The cytoskeleton modulates the adhesion of osteoclasts to bone and its subsequent resorption. These cells contain NADPH diaphorase activity, and free radicals influence bone resorption. The influence of Rac1, Rac2 and PAK1 on the cytoskeleton, resorbing activity and NADPH diaphorase activity of disaggregated rat osteoclasts was investigated by permeabilisation with saponin and introducing specific anti-Rac1, anti-Rac2 or anti-PAK1 antibodies. Rhodamine-phalloidin stain was used to identify actin in osteoclasts cultured on plastic slides, and the bone-slice method was used to measure resorption. Saponin permeabilisation did not affect the cytoskeletal organization or bone resorption. Anti-Rac antibodies caused dose- and time-dependent cytoskeletal changes. The osteoclasts rounded up and developed retraction fibers; actin rings were disrupted and large actin dots were seen at the periphery of the cells. Osteoclast resorptive activity was depressed after incubation with the antibodies. The total area resorbed by treated cells and the mean pit area were smaller than those of controls. Anti-PAK1 antibody caused similar changes. None of the antibodies altered the NADPH diaphorase activity. Thus, Rac-GTPases are present in rat osteoclasts and are involved in the organization of the actin cytoskeleton and in resorptive activity. These effects may be mediated by PAK1 kinase, but do not influence osteoclast NADPH diaphorase activity.

Actins↗

PubMed1999

Beta1 integrin antisense oligodeoxynucleotides: utility in controlling osteoclast function.

The involvement of beta1 integrins in osteoclast function has been investigated by utilising an antisense oligodeoxynucleotide (ODN) approach. 18-mer antisense and control phosphorothioate ODNs were made to a conserved internal region of beta1 integrin sequence (nucleotide positions 1634-1651 of the human beta1 fibronectin receptor). These were tested on rabbit osteoclasts for anti-adhesive and resorptive effects mediated by alphaVbeta3 and alpha2beta1, the major integrins of osteoclasts. Antisense, but not control, beta1 ODNs inhibited osteoclast adhesion to collagen-coated glass (by up to 70%), but not to glass coated with vitronectin, fibronectin or fibrinogen. Adhesion to dentine and subsequent resorption were also inhibited (up to 60%) in a sequence-specific manner. The mechanism of action was verified using both a melanoma cell line, DX3, which expresses multiple integrins at high level including alphaVbeta3 and alpha2beta1, and in a rabbit osteoclast marrow culture (BMC) system. Exposure of DX3 cells to antisense ODN for up to 48 hours reduced adhesion to FCS- and collagen-coated glass, and concomitantly inhibited beta1 protein expression assessed by FACS and Western blot analysis; expression of other integrin subunits, alphaV and beta3, was unaffected. Similarly, the beta1 protein levels in the BMC were reduced by > 75% without any effect on actin expression. These data reveal the utility of antisense ODNs in exploring osteoclast biology and further define the functional role of osteoclastic beta1 integrin(s).

Animals↗

PubMed2003

Molecular mechanisms underlying osteoclast formation and activation.

Osteoporosis is one of the leading causes of morbidity in the elderly and is characterized by a progressive loss of total bone mass and bone density. Bone loss in osteoporosis is due to the persistent excess of osteoclastic bone resorption over osteoblastic bone formation. Receptor activator of NFkappaB ligand (RANKL) critically regulates both osteoclast differentiation and activation. TRAFs appear to be central coupling molecules in the signal transduction pathways that regulate osteoclastogenesis, cathepsin K is the major mediator of osteoclastic bone resorption, and sex steroids and aging also affect osteoclastogenesis and osteoclast activity. However, bone homeostasis depends upon the intimate coupling of bone formation and bone resorption, wherein both osteoclasts and osteoblasts exert vital stimulatory and inhibitory effects upon each other via molecules such as RANKL, TGFbeta, PDGF, BMP2, and Mim-1. This review will highlight some of the major features of the complex circuit of cytokines, growth factors, and hormones that underlies the formation and function of osteoclasts and the dynamic equilibrium that marks the interaction between osteoclasts and osteoblasts.

Aged↗

PubMed2001

Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitf(mi/mi) mice.

Osteoclasts are multinucleated hematopoietic cells essential for bone resorption. Macrophage colony-stimulating factor (M-CSF) is critical for osteoclast development and function, although its nuclear targets in osteoclasts are largely unknown. Mitf and TFE3 are two closely related helix-loop-helix (HLH) transcription factors previously implicated in osteoclast development and function. We demonstrate that cultured Mitf(mi/mi) osteoclasts are immature, mononuclear, express low levels of TRAP, and fail to mature upon M-CSF stimulation. In addition, M-CSF induces phosphorylation of Mitf and TFE3 via a conserved MAPK consensus site, thereby triggering their recruitment of the coactivator p300. Furthermore, an unphosphorylatable mutant at the MAPK consensus serine is specifically deficient in formation of multinucleated osteoclasts, mimicking the defect in Mitf(mi/mi) mice. These results identify a signaling pathway that appears to coordinate cytokine signaling with the expression of genes vital to osteoclast development.

Amino Acid Motifs↗

PubMed2000

Higher osteoclastic demineralization and highly mineralized cement lines with osteocalcin deposition in a mandibular cortical bone of autosomal dominant osteopetrosis type II: ultrastructural and undecalcified histological investigations.

In this study we report on histological and ultrastructural investigations of the mandibular cortical bone in a case of autosomal dominant osteopetrosis type II complicated by mandibular osteomyelitis. Histologically, there was a marked increase in the number and size of osteoclasts on the inner bone surface. An undecalcified preparation showed a pair of deeply stained (highly demineralized) and stain-phobic (highly mineralized) layers on the bone surface just beneath the osteoclasts. The layers were incorporated into the bone matrix during the remodeling process as thickened cement lines. A contact microradiogram of the cortical bone revealed highly mineralized layers at the cement lines, which were closely correlated with immunohistochemical evidence of deposition of osteocalcin at the thickened cement lines. Ultrastructural examination showed that the osteoclasts had a typical clear zone, but they were deficient in ruffled border formation and had numerous lysosomal vacuoles containing dense substances. An electron-dense amorphous material layer was present on the bone surface just beneath the osteoclasts as well as at the cement lines. The layer was partly composed of a short fibrillar material, and it partially revealed the lamellar structure. Consequently, an osteoclastic malfunction might be primarily involved in the process of bone matrix resorption rather than demineralization, resulting in higher demineralization and abnormal material deposition on the bone surface and at the cement lines. Furthermore, evidence of active osteoclastic bone resorption with a brush border formation at the bone involved in the inflammatory lesion in this case suggests that the osteoclastic malfunction is influenced and recovered by a microenvironment such as inflammatory cytokines.

Bone Density↗

PubMed2001

Osteoprotegerin is produced when prostaglandin synthesis is inhibited causing osteoclasts to detach from the surface of mouse parietal bone and attach to the endocranial membrane.

Osteoclast differentiation and activation is controlled, at least in part, by the counterbalancing influences of osteoprotegerin ligand (OPGL) and osteoprotegerin (OPG). Nonsteroidal anti-inflammatory drugs have been shown to inhibit bone loss in vivo and bone resorption in vitro, and this is associated with a loss of osteoclasts from the bone surface. We test the hypothesis that OPG mediates the inhibition of osteoclast activity that occurs with indomethacin in the mouse calvaria. Recombinant human OPG, like indomethacin, was found to cause osteoclasts to detach from the bone surface and attach to the adjacent endocranial membrane (periosteum). Recombinant human OPG also inhibited the stimulatory effect of prostaglandin E2 (PGE2), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D3 (1,25D3) on osteoclast adhesion to bone after an incubation with indomethacin. A function-blocking antibody to OPG and soluble human OPGL both inhibited the effect of indomethacin, leaving active osteoclasts on the bone. OPG activity was detected in the culture medium from indomethacin-treated bones and PTH, PGE2, 1,25D3, and dexamethasone all inhibited the production of OPG activity. We conclude that, in the absence of specific stimulators of bone resorption, OPG is produced by the mouse calvaria in vitro, which inhibits bone resorption by causing osteoclasts to detach from the bone surface.

Animals↗

PubMed2001

The mouse osteopetrotic grey-lethal mutation induces a defect in osteoclast maturation/function.

The osteopetrotic grey-lethal (gl) mouse mutant displays many similarities to the human malignant autosomal-recessive form of osteopetrosis. In this study, we show that the gl osteopetrotic bone phenotype is characterized by the presence of numerous differentiated multinucleated osteoclasts. A significant increase in the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts was detected in vivo, suggesting induction of differentiation in the osteoclast lineage as a compensatory mechanism. These gl osteoclast cells demonstrated a defective cytoskeletal reorganization and an underdeveloped ruffled border, a membrane structure essential for active bone resorption. Accordingly, resorption activity of these cells is markedly impaired by four- to tenfold as evaluated with the pit formation assay. This low bone resorption in gl osteoclasts is highly reminiscent of the loss in key enzymes, V-ATPase or cathepsin-K, and in signaling factors, Src or TRAF-6, which were shown not to be significantly altered in gl osteoclasts. Thus, independently of a deficiency in V-ATPase, Src, cathepsin-K, and TRAF-6, the gl mutation results in increased number of osteoclasts, characterized by a disrupted cytoskeleton and an underdeveloped ruffled border.

Acid Phosphatase↗

PubMed2001

Bisphosphonate acts on osteoclasts independent of ruffled borders in osteosclerotic (oc/oc) mice.

We examined the effects of a third generation bisphosphonate [YM-175; disodium dihydrogen (cycloheptylamino)-methylene-1,1-bisphosphonate] on osteoclasts in osteosclerotic (oc/oc) mice to elucidate the cellular mechanism for incorporation of the bisphosphonate. Osteoclasts of oc/oc mice were in direct contact with bone matrix but devoid of ruffled borders. Tartrate-resistant acid phosphatase (TRAPase) showed spotty localization intercellularly, whereas vacuolar H(+)-ATPase (V-ATPase) immunoreactivity was observed homogeneously in the cytoplasm. Upon injection of bisphosphonate, most osteoclasts lost cell polarity and were detached from bone surfaces. The detached osteoclasts underwent apoptosis as characterized by condensation of chromatin, absence of Golgi apparatus, and formation of many vesicles in the cytoplasm. Both TRAPase and V-ATPase were evenly distributed in the cytoplasm. The pyknotic nuclei of osteoclasts revealed DNA fragments as evidenced by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling (TUNEL) method. The results indicate that osteoclasts lacking ruffled borders in oc/oc mice incorporated the bisphosphonate from a site different from ruffled borders and that bisphosphonate may directly affect osteoclasts without mediating its deposition to the bone matrix.

Animals↗