DigitalUM :: Browsing by Subject "Osteoclast"

Browsing by Subject "Osteoclast"

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Open Access
Bone allograft non-union is related to excessive osteoclastic bone resorption: A sheep model study
(Murcia : F. Hernández, 2006) Laird, R.K.; Pavlos, N.J.; Xu, J.; Brankov, B.; White, B.; Fan, Y.; Papadimitriou, J.M.; Wood, D.J.; Zheng, M.H.
Using a sheep femoral allograft model we have investigated the cellular and molecular mechanisms associated with non-union of bone allografts. Histomorphometric analysis revealed that allograft nonunions featured both marked increases in osteoclast (OC) numbers and total eroded bone surface as compared to allografts wich had undergone direct union. Three distinct cellular layers lying adjacent to the allograft bone surface were identified in all non-union cases. The outer or fibroblastic layer contained an abundance of fibroblasts and connective tissue. Circumscribing this layer was a band of synovial-like cells consisting mainly of large spindle-shaped mononuclear cells mixed with scattered round-shaped mononuclear cells. The third layer, which was directly juxtaposed to the allograft bone surface, consisted predominantly of multinuclear OCs which were positively identified by calcitonin receptor immunohistochemistry. Interestingly, in-situ hybridisation revealed that surrounding synovial-like cells in non-union allografts, expressed abundant gene transcripts for receptor activator NF-kB ligand (RANKL), a membrane bound factor critical for both the induction of OC activity and osteoclastogenesis. We propose that excessive bone resorption by host OCs contributes, at least partially, to the failure of bone allografts. The production of RANKL by synovial-like fibroblasts may be the driving force responsible for the elevated generation and activation of OCs. Based on such evidence novel therapeutic strategies for the treatment of non-union bone allografts using anti-bone resorbing agents may be devised.
Open Access
Canonical and non-canonical pathways of osteoclast formation
(Murcia : F. Hernández, 2009) Knowles, H.J.; Athanasou, N.A.
Physiological and pathological bone resorption is mediated by osteoclasts, multinucleated cells which are formed by the fusion of monocyte / macrophage precursors. The canonical pathway of osteoclast formation requires the presence of the receptor activator for NFkB ligand (RANKL) and macrophage colony stimulating factor (M-CSF). Noncanonical pathways of osteoclast formation have been described in which cytokines / growth factors can substitute for RANKL or M-CSF to induce osteoclast formation. Substitutes for RANKL include LIGHT, TNFa and interleukins 6, 11 and 8. M-CSF substitutes include vascular endothelial growth factor (VEGF), placental growth factor (PlGF), FLt-3 ligand and hepatocyte growth factor (HGF). These growth factors can also influence canonical (RANKL / M-CSFinduced) osteoclast formation. Both canonical and noncanonical pathways of osteoclast formation play a role in the formation of osteolytic lesions where there is increased osteoclast formation and activity, such as in giant cell tumour of bone.
Open Access
Cellular and molecular strategies for studying the regulation of bone resorption using the toothless (osteopetrotic) mutation in the rat
(Murcia : F. Hernández, 1997) Odgren, P.R.; Hermey, D.C.; Popoff, S.N.; Marks Jr., S.C.
The division of labor among cells of the skeleton is distinct and diverse and the regulation of these cells is interdependent. Osteoclasts are the cellular source of bone resorption and signals for their development and activation come, at least in part, from bone and other cells in the local environment. Studies of isolated cells have identified some factors in the developmental cascade of osteoclasts but there is little understanding of the sequence and local concentrations, not to mention other factors, needed for both the development of competent osteoclasts and for coordinated bone resorption. We review the skeletal biology of one osteopetrotic mutation in the rat, toothless, in which bone resorption is severely reduced because of a failure in the development and function of osteoclasts. Furthermore, we review the advantages and limitations of a relatively new method, differential display of mRNA (DD), that identifíes differences in gene expression in two or more populations of cells. We present a strategy and preliminary data for the application of DD to this mutation. We propose that application of this method to these and other skeletal diseases, with the appropriate controls and confirmations, will provide data about pathogenetic pathways and has a high probability for identifying new regulators of skeletal development and tumover.
Open Access
Cellular mechanisms of calcium phosphate ceramic degradation
(Murcia : F. Hernández, 1999) Heymann, D.; Pradal, G.; Benahmed, M.
Calcium phosphate (Cap) ceramics are widely used for bone substitution in orthopedic, maxillofacial and dental surgery. Many environmental factors are involved in the gradual degradation of calcium phosphate ceramic after implantation, including physicochemical processes (dissolution-precipitation) and the effects of various cell types. Several of these cell types degrade ceramics by, phagocytotic mechanisms (fibroblasts, osteoblasts, monocytes/macrophages) or by an acidic mechanism with a proton pump to reduce the pH of the microenvironment and resorb these synthetic substrates (osteoclasts). Various mesenchymal cells located at the implantation sites can induce the solubilization of Cap ceramics. Crystal-cell contacts were required to induce such crystal dissolution. Mesenchymal cells such as fibroblastic cells are also actively involved in the ceramic degradation process. In this context, Cap crystals underwent dissolution into the phagosome. If osteoclasts resorb Cap ceramics similarly to the natural bone, they possess a phagocytic capability. This phagocytosis mechanism consisted of three steps: crystal phagocytosis, disappearance of the endophagosome envelope membrane and fragmentation of phagocytosed crystals within the cytoplasm. Similar phenomenons have been observed during the phagocytic mechanism induced by monocytes/macrophages. The cellular mechanisms of Cap ceramic degradation are modulated by various parameters, such as the properties of the ceramic itself, the implantation sites and the presence of various proteins (cytokines, hormones, vitamins, ions, etc.). The cells involved in these mechanisms could intervene directly or indirectly through their cytokinelgrowth factor secretions and their sensitivity to the same molecules. This article reviews recent knowledge on the cellular mechanisms of calcium phosphate ceramic degradation.
Open Access
Human osteoclast ontogeny and pathological bone resorption
(Murcia : F. Hernández, 1999) Athanasou, N.A.; Sabokbar, A.
Monocytes and macrophages are capable of degrading both the mineral and organic components of bone and are known to secrete local factors which stimulate host osteoclastic bone resorption. Recent studies have shown that monocytes and macrophages, including those isolated from neoplastic and inflammatory lesions, can also be induced to differentiate into cells that show all the cytochemical and functional characteristics of mature osteoclasts, including lacunar bone resorption. Monocyte/macrophage- osteoclast differentiation occurs in the presence of osteoblasts/bone stromal cells (which express osteoclast differentiation factor) and macrophage-colony stimulating factor and is inhibited by osteoprotegerin. Various systemic hormones and local factors (eg cytokines, growth factors, prostaglandins) modulate osteoclast formation by controlling these cellular and humoral elements. Various pathological lesions of bone and joint (eg carcinomatous metastases, arthritis, aseptic loosening) are associated with osteolysis. These lesions generally contain a chronic inflammatory infiltrate in which macrophages form a significant fraction. One cellular mechanism whereby pathological bone resorption may be effected is through generation of increased numbers of bone-resorbing osteoclasts from macrophages. Production of humoral factors which stimulate mononuclear phagocyte-osteoclast differentiation and osteoclast activity is also likely to influence the extent of pathological bone resorption.
Open Access
Immunolocalization of MMP 2, 9 and 13 in prednisolone induced osteoporosis in mice
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Sun, Bao; Sun, Jing; Han, Xiuchun; Liu, Hongrui; Li, Juan; Du, Juan; Feng, Wei; Liu, Bo; Cui, Jian; Guo, Jie; Amizuka, Norio; Li, Minqi
Long-term use of glucocorticoids (GC) causes rapid bone loss and increases the risk of osteoporotic fractures. Matrix metalloproteinase (MMPs), the most prominent kind of proteases implicated in the proteolytic degradation of the extracellular matrix (ECM), have been reported to be involved in pathological process of GC induced osteoporosis. However, the underlining mechanisms are still unclear. The aim of this study was to investigate the spatial expression and the potential function of MMP 2, 9 and 13 in osteoporosis induced by prednisolone in the tibiae of mice. In this experiment, mice were given prednisolone (15 mg/kg body weight) in PBS intragastrically every other day, or only PBS as control. Two weeks later, mice were fixed with transcardial perfusion of 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4), and tibiae were extracted for histochemical analysis. Compared with control group, the number of TRAP-positive osteoclasts and the immunoreactivity of MMP 2, 9 and 13 were significantly increased in the trabecular bone of mice administered with prednisolone, leading to the decrease of trabecular bone volume. On the other hand, lighter eosin staining areas containing numerous empty lacunae of osteocytes and crevices were seen in the narrowing cortical bone. Furthermore, intense immunoreaction of MMP 2 and MMP 13 were found in the enlarged lacunae and the crevices, respectively. Taken together, we concluded that prednisolone administration induced the increase of MMP 2, 9 and 13 expressions, while MMP 2 and MMP 13 played essential roles in the osteocytic osteolysis and the early impaired areas in the cortical bone. Therefore, MMPs might be new potential therapeutic targets for prevention and treatment of glucocorticoid induced osteoporosis, especially osteocytic osteolysis.
Open Access
Induction of abundant osteoclast-like multinucleated giant cells in adjuvant arthritic rats with accompanying disordered high bone turnover
(Murcia : F. Hernández, 1998) Kuratani, T.; Nagata, K.; Kukita, T.; Hotokebuchi, T.; Nakasima, A.; Lijima, T.
The development of an in vivo system for investigating osteoclast differentiation is important because molecular events occurring in vivo can be observed during the differentiation of the authentic osteoclasts. In adjuvant arthritic rats, an experimental model of human rheumatoid arthritis, extensive bone resorption is observed in the distal diaphysis of the tibia. In the area of extensive bone resorption, it is always accompanied with clusters of numerous multinucleated giant cells (MGCs) as well as bone-resorbing osteoclasts. Here we characterized the morphological properties of these MGCs with the use of enzymehistochemical and immunohistochemical techniques. Extensive destruction but also a marked formation of the inner and outer bone surfaces were the predominant features in the tibiae of such arthritic rats 4 weeks after the adjuvant injection. Numerous MGCs were frequently clustered in the bone marrow spaces located apart from the bone matrices. Although the MGCs lacked ruffled borders, these cells were rich in mitochondria and vacuoles. These multinucleated cells revealed a positive reaction for tartrate-resistant acid phosphatase but a negative reaction for non-specific esterase staining. Most of these MGCs expressed the Kat l-antigen, an immunological marker specifically expressed on the cell surface of rat osteoclasts. In a dentin resorption experiment using a cluster of MGCs excised from the bone marrow tissues of the tibial distal diaphyses of rats with adjuvant arthritis, many resorption lacunae were formed on dentin slices after a 3-day culture. These results suggest that the majority of the MGCs are osteoclasts but not macrophage polykaryons
Open Access
Influence of metal ion solutions on rabbit osteoclast activities in vitro
(Murcia : F. Hernández, 2002) Rousselle, A.V.; Heymann, D.; Demais, V.; Charrier, C.; Passuti, N.; Baslé, Michael-Félix
The purpose of the present study was to compare the effects of various metal ions (aluminium, chromium, cobalt, gold, iron, strontium, titanium and vanadium) on rabbit osteoclast activities, with respect to their number, size, resorptive capacity and their capacity to release proteinases. Marked heterogeneous osteoclastic behaviour was observed early in culture with metal ions (24 h) in term of resorption parameters. In contrast, protease activities (cysteine-proteinase and metalloproteinase activities) were not modulated in our culture conditions. Aluminium, iron, gold and titanium reduced the number of osteoclasts significantly. Aluminium and gold had no effect on osteoclastmediated resorption on dentin-slices, although aluminium induced a greater number of very small lacunae. Titanium reduced only the mean surface area per lacunae, cobalt reduced the mean surface area of lacunae and increased their number, and iron reduced both parameters. Strontium had no effect on osteoclast formation and on total dentin slice surface resorbed. However, strontium increased the number of small lacunae formed on dentin-slices by osteoclasts. Chromium had no effect on osteoclast activities. These findings indicate that metal ions induce very early effects on osteoclasts, which can contribute to periprosthetic pathologies via different cellular mechanisms.
Open Access
Interaction between osteoblast and osteoclast: impact in bone disease
(Murcia : F. Hernández, 2004) Phan, T.C.A.; Xu, J.; Zheng, M.H.
The intercellular communication between osteoblasts and osteoclasts is crucial to bone homeostasis. Since Rodan and Martin proposed the control of osteoclasts by osteoblasts in the 1980s, many factors have been isolated from osteoblasts and shown to regulate the differentiation and function of osteoclasts. However, the mechanism by which osteoblasts regulate osteoclasts during bone remodelling is still unclear. On the other hand, it is well accepted that many metabolic bone diseases are associated with the disruption of the communication between osteoblast and osteoclasts. Thus, this review focuses on the cross-talk between osteoblasts and osteoclasts and its impact in bone disease.
Open Access
Potential synergies between matrix proteins and soluble factors on resorption and proteinase activities of rabbit bone cells
(Murcia : F. Hernández, 2001) Rousselle, A.V.; Damiens, C.; Grimaud, E.; Fortun, Y.; Padrines, M.; Passuti, N.; Heymann, D.
Human growth hormone (GH) has recently been found to stimulate osteoclastic resorption, cysteineproteinase and metalloproteinase activities (MMP-2 and MMP-9) in vitro via insulin-like growth factor-1 (IGF-1) produced by stromal cells. The present study investigated the effects of two extracellular matrix components (vitronectin and type-1 collagen) on hGHand hIGF-1-stimulated osteoclastic resorption and proteinase activities in a rabbit bone cell model. After 4 days of rabbit bone cell culture on dentin slices with vitronectin coating, hGH and hIGF-1 stimulated bone resorption and hIGF-1 upmodulated cysteine-proteinase activities. MMP-2 expression (but not resorption, cathepsin or MMP-9 activities) was upmodulated by hGH and hIGF-1 on dentin slices coated with type 1 collagen as compared to those without coating. Then, vitronectin was synergistic with hIGF-1 in the regulation of cysteine-proteinase production whereas collagen showed synergy with hGH and hIGF-1 in the regulation of MMP-2 production. Anti-avB3 totally abolished the effects of hGH and hIGF-1 on metalloproteinase release, but had no influence on cathepsin release. The results suggest that cysteine-proteinase modulation is not mediated by avB3 integrin (strongly expressed on osteoclastic surface) whereas the resorption process and metalloproteinase modulation are clearly'mediated by this integrin. Our finding about the collagen coating also suggests that hGH- and hIGF-1-stimulated MMP-2 activity are mediated, along with avB3 integrin, by another adhesion molecule.
Open Access
Rab3D a regulator of exocytosis in non-neuronal cells
(Murcia : F. Hernández, 2002) Millar, A.L.; Pavlos, N.J.; Xu, J.; Zheng, M.H.
Rab3D, a small Ras-like GTPase, is a key regulator of intracellular vesicle transport during exocytosis. It has been shown that Rab3 GTPases are abundant in cells with regulated secretory pathways and are thought to confer the specificity of docking and fusion during regulated exocytosis. Unlike other Rab3 isoforms, Rab3D is enriched in a number of nonneuronal tissues and is localised to secretory granules in the cytoplasm of these cells. The structure of Rab3D exhibits all of the conserved domains from the Rab family and also contains hypervariable N- and Cterminal regions. Rab3D undergoes post-translational isoprenylation and cycles between GDP- and GTPbound forms. Apart from the factors involved in the Rab activation cycle, few Rab3D effector proteins have been identified to date. Nevertheless, it has long been suggested that Rab3D plays a role in regulated exocytotic processes as well as apically directed transcytosis. This review summarises the recent work on the biological function, structural integrity and molecular interactions of Rab3D in non-neuronal cells.
Open Access
Structure and function of V-ATPases in osteoclasts: potential therapeutic targets for the treatment of osteolysis
(Murcia : F. Hernández, 2007) Xu, J.; Cheng, T.; Feng, H.T.; Pavlos, N.J.; Zheng, M.H.
Excessive activity of osteoclasts becomes manifest in many common lytic bone disorders such as osteoporosis, Paget’s disease, bone aseptic loosening and tumor-induced bone destruction. Vacuolar proton pump H+-adenosine triphosphatases (V-ATPases), located on the bone-apposed plasma membrane of the osteoclast, are imperative for the function of osteoclasts, and thus are a potential molecular target for the development of novel anti-resorptive agents. To date, the V-ATPases core structure has been well modeled and consists of two distinct functional domains, the V1 (A, B1, B2, C1, C2, D, E1, E2, F, G1, G2, G3, and H subunits) and V0 (a1, a2, a3, a4, d1, d2, c, c’ e1, e2 subunits) as well as the accessory subunits ac45 and M8-9. However, the exact configuration of osteoclast specific V-ATPases remains to be established. Inactivation of subunit a3 leads to osteopetrosis in both mice and man because of nonfunctional osteoclasts that are capable of acidifying the extracellular resorption lacuna. On the other hand, inactivation of subunits c, d1 and ac45 results in early embryonic lethality, indicating that certain subunits, such as a3, are more specific to osteoclast function than others. In osteoclasts, V-ATPases also cooperate with chloride channel protein CLC-7 to acidify the resorption lacuna. In addition, development of V-ATPases inhibitors such as bafilomycin A1, SB 242784 and FR167356 that selectively target osteoclast specific VATPases remains a challenge. Understanding the subunits of V-ATPase regulate osteoclast function might facilitate the development of novel and selective inhibitors for the treatment of lytic bone disorders. This review summarizes recent research developments in VATPases with particular emphasis on osteoclast biology.
Open Access
The histogenesis of giant cell tumour of bone: a model of interaction between neoplastic cells and osteoclasts
(Murcia : F. Hernández, 2001) Zheng, M.H.; Robbins, P.; Xu, J.; Huang, Liping; Wood, D.J.; Papadimitriou, J.M.
Giant cell tumour of bone (GCT) is a benign primary neoplasm of a bone characterised by distinctive clinical, radiological and pathological features. Females are slightly more often affected than males, and the majority of patients present between the ages of 20 and 50. GCT is locally aggressive and produces expansive and lytic lesions, most commonly in the epiphyses of long tubular bones. Histologically, it is composed of oval and spindle mononuclear cells, uniformly distributed amongst which are large multinucleated osteoclast-like giant cells. Although the term "Giant Cell Tumour" (and the erroneous historical term 'osteoclastoma') may imply that it is the multinucleated giant cells which are responsible for the proliferative capacity of the tumour, there is evidence that the stromal-like cells, the major component of the mononuclear celi population, represent the true neoplastic component of the neoplasm. The diagnosis and management of conventional GCT are often challenging and there is considerable current interest in its pathobiology. The precise histogenesis of GCT and the nature of its varying cellular constituents have remained a matter of some controversy. Factors influencing the clinical course and biological aggression of GCT are also unclear. In this selective review, the clinicopathological characteristics of GCT are summarised and current areas of interest in the study of the neoplasm are presented and discussed. Lastly, a hypothetical model of the mechanism of histogenesis and the biological behaviour of GCT is presented.
Open Access
The role of the bone marrow microenvironment in multiple myeloma
(Murcia : F. Hernández, 2005) De Raeve, H.; Vanderkerken, K.
Multiple myeloma (MM) is a malignant disease that results from an excess of monotypic plasma cells in the bone marrow (BM). This malignancy is characterised by complex karyotypic aberrancies. In 60% of all MM there are recurrent primary translocations involving the heavy chain gene locus. The MM cells strongly interact with the BM microenvironment, which is composed of endothelial cells, stromal cells, osteoclasts, osteoblasts, immune cells, fat cells and the extracellular matrix. This interaction is responsible for the specific homing in the BM, the proliferation and survival of the MM cells, the resistance of MM cells to chemotherapy, the development of osteolysis, immunodeficiency and anaemia. New therapeutic agents target both the MM, as well as the interaction MM cell – BM microenviroment.
Open Access
Treatment with tacrolimus enhances alveolar bone formation and decreases osteoclast number in the maxillae: A histomorphometric and ultrastructural study in rats
(Murcia : F. Hernández, 2008) Andia, Denise Carleto; Nassar, Carlos Augusto; Oehlmeyer Nassar, Patricia; Rodrigues Guimarães, Morgana; Cerri, Paulo Sérgio; Spolidorio, Luis Carlos
Recent studies have suggested that tacrolimus monotherapy is a beneficial therapeutic alternative for the normalization of cyclosporin-induced bone loss in animal models and humans. The mechanism accounting for this action is unclear at present. In the present study, we attempted to determine the effect of tacrolimus monotherapy on alveolar bone using histological, histomorphometrical and transmission electron microscopy (TEM). Groups of rats (n=10 each) were treated with either tacrolimus (1mg/kg/day, s.c.) or drug vehicle for 60 days. Fragments containing maxillary molars were processed for light microscopy to investigate the alveolar bone volume, trabecular separation, number of osteoclasts and osteoblasts, and transmission electron microscopy to investigate their ultrastructural basic phenotype. Treatment with tacrolimus monotherapy during 60 days may induce increases in alveolar bone volume (BV/TV,%; P<0.05) and a non-significant decrease in trabecular separation (Tb.Sp,mm; P>0.05), represented by a decrease in osteoclast number (N.Oc/BS; P<0.05) and maintenance of osteoblast number (N.Ob/BS; P>0.05). Osteoblasts were often observed as a continuous layer of active cells on the bone surface. Osteoclasts appeared to be detached from the resorbed bone surface, which was often filled by active osteoblasts and collagen-rich matrix. Moreover, osteoclasts in the treated group were frequently observed as inactive cells (without ruffled border, clear zone and detached from the bone surface). Within the limits of the present study, we conclude that tacrolimus leads to an increase in alveolar bone formation, which probably exerts action on osteoclasts. Tacrolimus could, therefore, play a crucial role in the control of both early osteoclast differentiations from precursors, as well as in functional activation.
Open Access
Ultrastructural evidence in vitro of osteoclast-induced degradation of calcium phosphate ceramic by simultaneous resorption and phagocytosis mechanisms
(Murcia : F. Hernández, 2001) Heymann, D.; Guicheux, J.; Rousselle, A.V.
Osteoclasts are physiological polykaryons specialized in the resorption of calcified tissue. In the context of the clinical use of calcium-phosphate (Cap) ceramics as bone substitutes, this study used transmission electron microscopy to investigate the in vitro mechanisms of Cap ceramic degradation by osteoclastic cell types. Osteoclasts cultured on Cap ceramic developed typical ultrastructural features of bone osteoclasts, such as a polarized dome shape, a clear zone and a ruffled border. Modification of the shape and density of Cap crystals under the ruffled border indicated an acidic microenvironment. Moreover, osteoclasts were able to degrade ceramic by simultaneous resorption and phagocytosis mechanisms. Phagocytosis did not alter the ability of osteoclasts to resorb Cap ceramic. The phagocytosis mechanism consisted of three steps: crystal phagocytosis, disappearance of the endophagosome envelope membrane and fragmentation of phagocytosed crystals within the cytoplasm. The common mechanism of phagocytosis described here is similar to that observed with the monocyte/macrophage lineage, confirming that osteoclasts are part of the mononuclear phagocyte system. Osteoclasts are thus clearly involved in Cap degradation by means of resorption and phagocytosis
Open Access
ß-Galactosidase staining on bone marrow. The osteoclast pitfall
(Murcia : F. Hernández, 2007) Kopp, H.G.; Hooper, A.T.; Shmelkov, S.V.; Rafii, S.
The enzyme ß-galactosidase, encoded by the bacterial gene lac-Z, is commonly used as a histochemical reporter to track transplanted cells in vivo or to analyze temporospatial gene expression patterns by coupling expression of specific target genes to ßgalactosidase activity. Previously, endogenous ßgalactosidase activity has been recognized as a confounding factor in the study of different soft tissues, but there is no description of the typical background on bone marrow sections when using the chromogenic substrate 5-Bromo-4-chloro-3-indolyl ß-D-Galactoside (X-Gal). In this report, we show that osteoclasts in bone marrow sections specifically and robustly stain blue with X-Gal. This leads to a typical background when bone marrow is examined that is present from the first day post partum throughout the adult life of experimental mice and can be confused with transgenic, bacterial ßgalactosidase expressing hematopoietic or stromal cells. Experimental variations in the X-Gal staining procedure, such as pH and time of exposure to substrate, were not sufficient to avoid this background. Therefore, these data demonstrate the need for strenuous controls when evaluating ß-galactosidase positive bone marrow cells. Verifiable bacterial ß-galactosidase positive bone marrow cells should be further identified using immunohistological or other approaches. Specifically, ßgalactosidase positive hematopoietic or stromal cells should be proven specifically not to be osteoclasts by costaining or staining adjacent sections for specific markers of hematopoietic and stromal cells.

Browsing by Subject "Osteoclast"

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