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Results for “Integrin alphaVbeta3”

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PubMed1999

Development and characterization of a human in vitro resorption assay: demonstration of utility using novel antiresorptive agents.

A human in vitro resorption assay has been developed using osteoclastoma-derived osteoclasts and used to evaluate novel antiresorptive agents including antagonists of the alphavbeta3 integrin, and inhibitors of cathepsin K and the osteoclast ATPase. The potency of novel compounds in the in vitro resorption assay correlates with functional assays for each class of inhibitor: the human alphavbeta3-mediated cell adhesion assay for the vitronectin receptor antagonists (r2 = 0.82), the chick osteoclast vacuolar ATPase enzyme assay for the H+-ATPase inhibitors (r2 = 0.77) and the recombinant human cathepsin K enzyme assay for the cathepsin K inhibitors (r2 = 0.80). Cell suspensions, rich in osteoclasts, are prepared by collagenase digestion of the tumor tissue. These cells can be stored long-term in liquid nitrogen and upon thawing maintain their bone-resorbing phenotype. The cryopreserved cells can be cultured on bovine cortical bone for 24-48 h and resorption can be measured by either confocal microscopy or biochemical assays. The resorptive activity of osteoclasts derived from a number of tumors can be inhibited reproducibly using a number of mechanistically unique antiresorptive compounds. In addition, the measurement of resorption pits by laser confocal microscopy correlates with the release of type I collagen C-telopeptides or N-telopeptides, as measured by enzyme-linked immunosorbent assay. Resorption can be measured reproducibly using a 48-h incubation of osteoclasts on bone slices, or a 24-h incubation with bone particles. This in vitro human osteoclast resorption assay provides a robust system for the evaluation of inhibitors of osteoclastic function that may be developed for the treatment of metabolic bone diseases such as osteoporosis.

Adenosine Triphosphatases↗

PubMed2005

Modulation of chondrocyte adhesion to collagen by echistatin.

Primary chondrocytes from quail embryo epiphysis (quail epiphyseal chondrocytes, QEC) can grow either in suspension or in monolayer. In this study, the adhesion of QEC to collagen II was used as a model to study the regulation of the ligand-binding activity of integrin receptors that allows these cells to undergo a rapid transition from suspension to an adherent state. Preincubation of suspension QEC (QECSP) with the disintegrin echistatin increased by 40% their adhesion to collagen II. An inverse relationship between immobilized collagen density and echistatin-induced increase of chondrocyte adhesion was observed, thus suggesting that the disintegrin acts by increasing the ligand-binding affinity of collagen receptor(s). Further, echistatin activity does not appear to depend upon a direct binding of the disintegrin to collagen receptor(s). In fact, immobilized anti-beta1 antibodies, but not immobilized echistatin, served as effective binding sites for QECSP. Echistatin failed to stimulate chondrocyte adhesion to collagen in the presence of metabolic inhibitors, while an activating anti-beta1 antibody was still effective. Thus, echistatin may promote cell adhesion by interfering with energy-dependent signals that keep the collagen receptor(s) in a low-affinity state. Adhesion experiments performed in the presence of pharmacological inhibitors indicate that phosphatidyl inositol 3-kinase (PI3-K)/protein kinase C (PKC) and protein kinase A (PKA) pathways may transmit opposing signals on chondrocyte adhesion, and that collagen receptors are kept in a low-affinity state by PI3-kinase/PKC signalling. Since echistatin is a high-affinity ligand for alphavbeta3 integrin, the effect of the function-blocking anti-alphavbeta3 antibody LM609 was investigated. Like echistatin, LM609 stimulated chondrocyte adhesion to collagen and failed to support their attachment. Therefore, our data suggest that alphavbeta3-antagonists might regulate the binding activity of the beta1 collagen receptor, which in turn leads to the rapid transition of chondrocytes from suspension to an adherent state.

Animals↗

PubMed2003

Generation of a monoclonal antibody to a cryptic site common to both integrin beta1 as well as gelatinase MMP9.

Integrins are one class of cell surface receptors that have been implicated in the regulation of a diverse set of cellular processes, including cell adhesion, migration, and invasion as well as gene expression, differentiation, and signal transduction. Cellular invasion not only requires the adhesive properties of integrins but also the proteolytic properties of matrix-degrading enzymes, such as the metalloproteinases (MMPs). Previous studies have shown that integrin alphavbeta3 is a receptor for MMP2, localizing its proteinase activity to the cell surface, ultimately leading to site-specific extracellular matrix (ECM) degradation. Here we develop reagents to investigate the possibility of an interplay between MMP9 and integrin alpha5beta1. With the use of EV22 viral studies, the tetrapeptide sequence, LRSG, was shown to be a dimerizing sequence mediating beta1 integrin binding to EV22. The same study also showed that cellular infection could be halted with the use of LRSG-containing peptides. In a later study, in an effort to isolate inhibitors of the MMP family, LRSG sequence was identified as one capable of binding MMP9. Interestingly, MMP9 contains an LRSG sequence, raising the possibility that MMP9 binds the cell surface via beta1 integrins through the dimerizing LRSG motif. We used the LRSG-containing sequence from beta1 integrins as an antigen to generate the monoclonal antibody (MAB) FM155 in the mouse model. MAB FM155 will help identify a cryptic epitope, LRSG, and its role in matrix remodeling as well as tumor growth, cancer cell migration, and angiogenesis.

Amino Acid Sequence↗

PubMed2005

Modulation of alpha4 integrin mRNA levels is coupled to deficits in vasomotor function in rat arterioles by allylamine.

Allylamine, a selective cardiovascular toxin that induces oxidative stress, is known to alter expression of extracellular matrix and cell adhesion proteins that are central to arterial remodeling. Our goals were to determine whether AAM treatment in rats modulates integrin/matrix-dependent arteriolar function, and to what extent integrin expression correlated to these alterations. Integrins are transmembrane proteins that facilitate mechanical and molecular signaling between the extracellular matrix and cytoskeleton, and so are suitable candidates for involvement in phenotypic and functional alterations of smooth muscle in response to oxidative stress. Arg-Gly-Asp (RGD) and Leu-Asp-Val (LDV), two integrin-binding motifs found in ECM proteins such as collagens and fibronectin, are known to interact with integrins alphavbeta3 and alpha4beta1, respectively. Previously, we found that RGD containing peptides induce vasodilation through alphavbeta3, while LDV containing peptides induce vasoconstriction through alpha4beta1 of normal rat cremasteric arterioles. In allylamine-treated rats (AAM), the vasomotor response to LDV, but not RGD, was attenuated in a dose-dependent manner. To determine whether changes in integrin subunit mRNA levels correlated with these functional changes, we performed reverse transcription and Real-time PCR for alpha4 and beta3 integrin subunits on RNA isolated from single, first-order cremasteric arterioles. AAM treatment caused a dose-dependent decrease in alpha4 mRNA expression, but not beta3 mRNA expression, suggesting that the changes in vasomotor activity to LDV peptides may be attributable in part to reduced alpha4 expression upon exposure to AAM. These data are supported by similar decreases in alpha4integrin cell surface protein expression in cultured vascular smooth muscle cells treated either in vivo and in vitro with AAM.

Allylamine↗

PubMed2006

Antitumor effect of RGD-4C-GG-D(KLAKLAK)2 peptide in mouse B16(F10) melanoma model.

Vasculature targeting agents have been tested as cancer therapeutics for the past few years. Such therapy could be accomplished using, for example, bifunctional (two-domain) peptides. RGD-4C-GG-D(KLAKLAK)2, a peptide designed by Ellerby and coworkers (1999) (full sequence: ACDCRGDCFCGGKLAKLAKKLAKLAK), binds selectively to alphaVbeta3 integrin receptors expressed in tumor neovasculature and, after internalization, effectively induces apoptosis of endothelial cells. The aim of this study was to examine if RGD-4C-GG-D(KLAKLAK)2 would efficiently target cells, among them B16(F10), that overexpress alphaVbeta3 receptors, and whether it would be suitable for therapeutic treatment of primary B16(F10) murine melanoma tumors. Thus, the peptide would target two distinct tumor compartments: that formed by endothelium of blood vessels and that made up of neoplastic cells. The therapeutic peptide was recognized and did induce apoptosis in B16(F10) cell line. Tumor growth inhibition was observed following direct intratumoral administration. However, cessation of peptide administration led to rapid tumor growth and death of the animals.

Amino Acid Sequence↗

PubMed2004

The discovery of VLA-4 antagonists.

Starting with a cyclic peptide of moderate potency as a VLA-4 antagonist, highly potent and conformationally defined cyclic peptides were developed incorporating a constrained tyrosine and an achiral Asp-Pro spacer. N-Acyl phenylalanine derivatives were also discovered to have VLA-4 antagonist activity. During the course of development of this series, we found that the active acylphenylalanines mimic the pharmacophores present in the cyclic peptides and hypothesized that they bind to the same site on VLA-4. This insight guided our optimization strategy. Based on the emerging SAR, as well as insights from the recent X-ray crystal structure of the integrin alphavbeta3 bound to a RGD containing cyclic peptide, we propose a binding model for these compounds.

Humans↗

PubMedDate not supplied

Targeting Beta-3 integrin using a linear hexapeptide labeled with a near-infrared fluorescent molecular probe.

Biomolecules containing the RGD peptide sequence are known to bind integrins with high affinity. Studies of hexa-and hepta-peptides labeled with a near-infrared fluorescent probe (cypate) showed that rearranging the glycine in a linear RGD peptide sequence to form the GRD analogue favored the uptake of the GRD compound by alphavbeta3 integrin receptor (ABIR)-positive A549 tumor cells and tissue. The internalization of the GRD compound in A549 cells and tumor uptake in mice were inhibited by ABIR-avid peptides, suggesting its recognition by this receptor. Further studies with functional blocking antibodies and beta3 knockout cells revealed that beta3 integrin mediates the internalization of the cypate-GRD peptide. Molecular modeling studies supported preferential interaction of the probe with the beta3 subunit of integrins relative to the alphav subunit. The results demonstrate that the cypate-GRD peptide targets beta3 integrin, thereby providing a strategy to monitor drug delivery and efficacy, and physiopathologic processes mediated by this protein.

Animals↗

PubMed2003

Inhibitory effect of salmosin, a Korean snake venom-derived disintegrin, on the integrin alphav-mediated proliferation of SK-Mel-2 human melanoma cells.

We have investigated the inhibitory effect of salmosin on integrin-mediated human tumour cell proliferation. SK-Mel-2 human melanoma cell adhesion to denatured collagen or vitronectin was found to be significantly and statistically inhibited by salmosin in a dose-dependent manner (P<0.05). Moreover, the binding of SK-Mel-2 cells to salmosin-coated plates was specifically disrupted by anti-integrin alphav monoclonal antibody at 8 microg mL(-1), but not by anti-integrin monoclonal antibody. These findings indicated that salmosin inhibited the adhesion of SK-Mel-2 cells to denatured collagen by specifically blocking integrin alphav. The proliferation of SK-Mel-2 cells on a denatured collagen-coated plate was statistically and significantly inhibited by salmosin induced apoptosis in a dose-dependent manner (P<0.05). Anti-integrin alphav monoclonal antibody, anti-integrin alphavbeta3 monoclonal antibody, and synthetic RGD peptide also suppressed SK-Mel-2 cell proliferation. Several lines of experimental evidence strongly suggested that the inhibition of SK-Mel-2 cell proliferation by salmosin was due to the induction of apoptosis via the blocking of integrin alphav-mediated cell survival.

Apoptosis↗

PubMed2004

Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis.

OBJECTIVE: Neovascularization, with an increased number of synovial vessels with a characteristic morphology, seems to contribute to the progression of psoriatic arthritis (PsA). Accordingly, angiogenesis may be an important therapeutic target in PsA. The aim of this study was to analyze the effects of infliximab on angiogenesis in the synovial membrane of patients with PsA who responded to this therapy. METHODS: The study group comprised 9 patients with PsA who were selected for the presence of active polyarthritis (including knee synovitis) despite methotrexate therapy. Clinical and biologic evaluations were performed at each visit. Arthroscopy and synovial biopsies were performed at week 0, before infliximab therapy was initiated, and at week 8, after administration of 3 intravenous infusions of infliximab (5 mg/kg). We used immunohistochemistry to identify changes in infiltrating cells and in the angiogenesis modulators alphavbeta3 integrin, vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang-2), flt-1 (VEGF receptor 1 [VEGFR-1]), kinase insert domain receptor [KDR]/flk-1 (VEGFR-2), and stromal cell-derived factor 1 (SDF-1). Neovascularization was assessed by automated histomorphometry of CD31+ vessels and by measuring alphavbeta3 expression. RESULTS: Rapid and significant clinical and biological improvement were observed after treatment in all patients. In the synovium, infliximab therapy induced a significant reduction in macrophages, the CD31+ vascular area, alphavbeta3+ neovessels/Ulex europaeus agglutinin+ vessels, VEGF and its receptor KDR/flk-1 (VEGFR-2), and SDF-1+ vessels. Expression of flt-1 (VEGFR-1), and SDF-1 in lining cells showed a nonsignificant reduction, whereas expression of Ang-2 increased. In 3 patients, reverse transcription-polymerase chain reaction confirmed the changes in some of these markers at the messenger RNA level. CONCLUSION: These results show consistent changes in several factors involved in angiogenesis regulation, in parallel with the clinical response to infliximab in patients with PsA. The pattern of reduced VEGF with increased Ang-2 suggests vascular regression as a potential mechanism underlying the antiangiogenic effect of infliximab.

Antibodies, Monoclonal↗

PubMed2006

c7E3 Fab inhibits human tumor angiogenesis in a SCID mouse human skin xenograft model.

The alphavbeta3 integrin plays an important role in tumor growth and angiogenesis. Inhibition of this receptor by intact bivalent antibodies has been shown to inhibit angiogenesis and tumor growth. In this study we tested the chimeric Fab of 7E3 (c7E3 Fab), an antibody reactive with human platelet GPIIb/IIIa and alphavbeta3 to determine if it would inhibit in vivo angiogenesis and tumor growth in a SCID mouse/human skin tumor growth and angiogenesis model. c7E3 Fab inhibited human tumor angiogenesis and tumor growth. These data suggest monovalent antibody fragments devoid of antibody effector function can have efficacy in preclinical models of angiogenesis.

Abciximab↗

PubMed2005

Enamel matrix derivative is a potent inhibitor of breast cancer cell attachment to bone.

This study examined whether enamel matrix derivative (EMD) inhibits the adhesion of cancer cells to bone. A typical breast cancer cell line, MCF-7, was used. Conditioned human osteosarcoma cell (Saos-2) medium was used as extracellular bone matrix (ECBM) to measure cell attachment. MCF-7 cells were incubated on ECBM-coated culture plates with or without soluble EMD, Arg-Gly-Asp (RGD) sequence blocking peptides, recombinant bone sialoprotein (rBSP), or specific integrin antibodies, and the attached cells were quantified using toluidine blue staining. EMD markedly reduced the attachment of MCF-7 cells to ECBM in a dose-dependent manner. An RGD peptide (GRGDSP) and recombinant BSP inhibited cell attachment to the same degree as EMD. Similarly, anti-alphavbeta3 integrin antibody strongly reduced cell attachment, whereas anti-alphavbeta5 and anti-beta1 integrin antibodies had less marked effects on cell attachment. These results show that EMD inhibits MCF-7 cell attachment to a bone matrix and that it might be useful as an anti-adhesive agent for breast cancer cells to bone in vivo.

Antibodies, Monoclonal↗

PubMed2003

Differential expression of beta3 integrin gene in chick and mouse cranial neural crest cells.

RNA in situ hybridization on early chicken embryos revealed that the beta3 integrin gene started to be expressed after Hamburger and Hamilton (HH) stage 6 in the presumptive epidermis adjacent to the neural plate, before closure of the neural tube. The beta3 integrin gene was also strongly expressed in cephalic neural crest cells at the same stage in which they begin their migration but disappeared progressively in these cells along the route they take to the branchial arches. The gene was weakly expressed in the differentiating cranial neural crest cells. The alphaVbeta3 integrin protein complex was also mainly detected in the migratory cephalic neural crest cells. However, during early mouse embryogenesis and in contrast to the chick, the beta3 integrin gene was expressed in the foregut diverticulum and in the heart and not in the cephalic neural crest cells. Therefore, the difference in the beta3 integrin expression suggests that mouse and chicken cranial neural crest cells may have distinct integrin requirements during their ontogenesis.

Animals↗

PubMed1996

Alternative adhesion sites in human fibrinogen for vascular endothelial cells.

Fibrinogen mediates endothelial cell adhesion, spreading, and angiogenesis through integrin alphavbeta3. Previous studies by several investigators have suggested that the Arg-Gly-Asp (RGD) site at position 572-574 on the alpha chain of human fibrinogen can bind to alphavbeta3. However, this RGD sequence is absent in fibrinogen from most other species, including bovine, hamster, monkey, mouse, pig, and rat fibrinogen. In these species, an RGD site exists at the equivalent of position alpha252-254, which has the sequence RGG in humans. In addition, the role of an integrin binding site on the gamma chain at position 400-411 has been an issue of controversy. In the present studies, recombinant fibrinogen molecules with mutations in the potential endothelial cell binding sites have been used to test the role of these sites directly. The results show that the RGD at alpha572-574 is the primary adhesion site, and that the gamma chain site plays no significant role. Human and bovine plasma fibrinogens were also assayed for their ability to support adhesion of human and bovine vascular endothelial cells. The results show that although the two types of fibrinogen have RGD sequences at widely divergent sites, there is no significant difference in their ability to support endothelial cell adhesion. Furthermore, a chimeric human fibrinogen molecule with an RGD sequence at the bovine site, position alpha252-254, also supported adhesion. These results indicate that an RGD site in human fibrinogen at either position alpha252-254 or position alpha572-574 can mediate endothelial cell adhesion.

Amino Acid Sequence↗

PubMed1997

Muscle beta1D integrin reinforces the cytoskeleton-matrix link: modulation of integrin adhesive function by alternative splicing.

Expression of muscle-specific beta1D integrin with an alternatively spliced cytoplasmic domain in CHO and GD25, beta1 integrin-minus cells leads to their phenotypic conversion. beta1D-transfected nonmuscle cells display rounded morphology, lack of pseudopodial activity, retarded spreading, reduced migration, and significantly enhanced contractility compared with their beta1A-expressing counterparts. The transfected beta1D is targeted to focal adhesions and efficiently displaces the endogenous beta1A and alphavbeta3 integrins from the sites of cell-matrix contact. This displacement is observed on several types of extracellular matrix substrata and leads to elevated stability of focal adhesions in beta1D transfectants. Whereas a significant part of cellular beta1A integrin is extractable in digitonin, the majority of the transfected beta1D is digitonin-insoluble and is strongly associated with the detergent-insoluble cytoskeleton. Increased interaction of beta1D integrin with the actin cytoskeleton is consistent with and might be mediated by its enhanced binding to talin. In contrast, beta1A interacts more strongly with alpha-actinin, than beta1D. Inside-out driven activation of the beta1D ectodomain increases ligand binding and fibronectin matrix assembly by beta1D transfectants. Phenotypic effects of beta1D integrin expression in nonmuscle cells are due to its enhanced interactions with both cytoskeletal and extracellular ligands. They parallel the transitions that muscle cells undergo during differentiation. Modulation of beta1 integrin adhesive function by alternative splicing serves as a physiological mechanism reinforcing the cytoskeleton- matrix link in muscle cells. This reflects the major role for beta1D integrin in muscle, where extremely stable association is required for contraction.

Actins↗

PubMed1998

The actin cytoskeleton and integrin expression in the recovery of cell adhesion after oxidant stress to a proximal tubule cell line (JTC-12).

This study examines the role of the actin cytoskeleton and integrin expression in the recovery of cell adhesion in the proximal tubule cell line JTC-12 after peroxide injury. The cells were exposed to 10, 20, or 50 mM hydrogen peroxide for 10 min and then allowed to recover. Viability measurements by trypan blue exclusion confirmed that the injury was largely nonlethal with 85% viability at 1 h even at 50 mM peroxide. ATP levels fell immediately after the peroxide incubation in all groups to approximately 10% of normal, but already showed some recovery by 1 h and full recovery in the 10 and 20 mM groups by 24 h. Cell adhesion to extracellular matrix immediately after injury was depressed at 20 and 50 mM peroxide, but by 12 h was abnormal only at 50 mM peroxide and at 24 h was essentially normal at all peroxide concentrations. Immediately after exposure to 10 mM peroxide, there were subtle abnormalities in the actin cytoskeleton (thickening of fibrils) as assessed by phalloidin staining, with more pronounced effects at 20 and 50 mM. At 1 h, many cells showed collapse of the actin cytoskeleton to the periphery. There was some recovery at 4 h; by 12 h, the actin cytoskeleton showed further recovery, although was still abnormal (coarsened microfilaments), especially at 20 and 50 mM peroxide. By 24 h, the actin cytoskeleton showed only subtle coarsening. Integrin surface expression was assessed by flow cytometry. The alpha6 subunit on cells exposed to 20 mM peroxide was unchanged at 1 h and 4 h, but by 12 h had increased to 118.5+/-4.5% and by 24 h to 146+/-13.4% of control levels. The expression of the beta1 and alphaVbeta3 integrins remained unchanged. Thus, despite coarsening of the actin cytoskeleton and depressed ATP levels, cell adhesion recovered from oxidant stress. Abnormal cell adhesion after injury was not a consequence of a decrease in integrin expression, and recovery of cell adhesion was not a consequence of the modest and selective increase in integrin expression.

Actins↗

PubMed2004

Expression of alphav, alpha4, alpha5 and beta3 integrin subunits, fibronectin and vitronectin in goat peri-implantation.

Integrins are glycoprotein heterodimers located in the cell membranes that stimulate intercellular adhesion and act as extracellular matrix (ECM) protein receptors. Although integrins have been detected in the implantation sites of various species, little is known about their participation in ruminant non-invasive placentation. The objective of this study was the detection of alphav, alpha4, alpha5, beta1 and beta3 integrin subunits and of two of their ligands, fibronectin and vitronectin, to determine their participation in the caprine peri-implantation process. On Day 21 post-coitum (pc), endometrial epithelium and trophoblastic cells showed an intense alphav and beta3 integrin subunits expression and moderate staining for alpha4 and alpha5. On Day 23 pc, integrin expression decreased noticeably and only a weak staining of alpha4 and beta3 integrin subunits were observed. No beta1 integrin subunit expression was detected on either of the days studied. Fibronectin (FN) expression in trophectodermic and endometrial epithelium was weak or moderate on the days studied while vitronectin (VN) expression in the same tissues was moderate or strong on Day 21 pc but decreased on Day 23 pc. These results suggest that alphavbeta3 integrin, alpha4 and alpha5 subunits, VN and FN are expressed in caprine endometrium and blastocyst and may play a role in the cascade of the implantation process.

Animals↗

PubMed1998

Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging.

Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin alphaVbeta3, has been shown to correlate with tumor grade. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial alphaVbeta3 via the LM609 monoclonal antibody. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angiogenic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of alphaVbeta3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.

Animals↗

PubMed2006

Osteoclasts and integrins.

The osteoclast is the unique bone resorptive cell that accomplishes its mission by forming an isolated acidified microenvironment between itself and the bone surface. Creation of this compartment is the first step in bone degradation and establishes that an intimate physical relationship must exist between the osteoclast and bone. Thus, identification of the mechanisms by which the osteoclast attaches to bone is essential to understanding how the cell degrades skeletal tissue. Our studies have investigated whether absence of the alphavbeta3 integrin modifies the ability of c-Fms to induce Rho GTPases, and the implications for formation of the osteoclast cytoskeleton.

Animals↗