Osteoclast motility: Putting the brakes on bone resorption

doi:10.1016/j.arr.2009.09.005

Ageing Research Reviews

Volume 10, Issue 1, January 2011, Pages 54-61

https://doi.org/10.1016/j.arr.2009.09.005 Get rights and content

Abstract

As the skeleton ages, the balanced formation and resorption of normal bone remodeling is lost, and bone loss predominates. The osteoclast is the specialized cell that is responsible for bone resorption. It is a highly polarized cell that must adhere to the bone surface and migrate along it while resorbing, and cytoskeletal reorganization is critical. Podosomes, highly dynamic actin structures, mediate osteoclast motility. Resorbing osteoclasts form a related actin complex, the sealing zone, which provides the boundary for the resorptive microenvironment. Similar to podosomes, the sealing zone rearranges itself to allow continuous resorption while the cell is moving. The major adhesive protein controlling the cytoskeleton is αvβ3 integrin, which collaborates with the growth factor M-CSF and the ITAM receptor DAP12. In this review, we discuss the signaling complexes assembled by these molecules at the membrane, and their downstream mediators that control OC motility and function via the cytoskeleton.

Section snippets

Skeletal aging

Maintenance of skeletal integrity is an important part of healthy aging. In both women and men, peak bone mass is attained in early adulthood, and significant declines occur as levels of sex hormones drop, leading to osteoporosis. In the mature skeleton, the process of remodeling constantly replaces bone elements, with an average turnover interval of about 10 years. The basic multicellular unit (BMU) consists of the coupled activity of osteoclasts (OCs), which remove bone, and osteoblasts

OC differentiation

The only cell capable of removing both the organic and inorganic matrices of bone is the OC, a multinucleated cell derived from fusion of bone marrow cells in the monocyte/macrophage lineage (Ikeda et al., 1998). Like other monocyte/macrophages, they require the growth factor M-CSF to interact with its receptor c-Fms, a receptor tyrosine kinase (RTK), which provides proliferative signals to the precursors as well as survival signals for mature cells (Ross and Teitelbaum, 2005). Differentiation

Resorptive machinery of an active OC

Mature OCs polarize when attached to bone, which occurs via the αvβ3 integrin that recognizes matrix proteins such as bone sialoprotein and osteopontin. The integrin and an associated cytoskeletal complex (discussed below) form a sealing zone, a ring-shaped boundary where the OC membrane is very closely apposed to the bone surface, defining an isolated extracellular space between the OC and the bone surface. In fact, at least in vitro, individual OCs can form more than one sealing zone. Bone

Podosomes: organizing principle of the OC cytoskeleton

The primary component of the cytoskeleton is F-actin, and the OC has a distinct actin complex known as the podosome which mediates its attachment to the bone matrix (Destaing et al., 2003). Podosomes contain an F-actin core that also concentrates actin regulatory proteins including cortactin, Wiskott Aldrich Syndrome Protein (WASP), WASP Interacting Protein (WIP), Arp2/3, and gelsolin, as well as CD44, another adhesion receptor. Surrounding the core are adhesion-associated proteins such as

M-CSF: a migratory stimulus and actin regulator

In most cells, migration involves directed protrusion at the leading edge through localized polymerization of actin, forming a membrane extension called a lamellipodium. Integrin-mediated adhesion to the substrate stabilizes adhesions, allowing cells to generate tension and the contractile force required for cell movement. Adhesion is then released at the rear of the cell to allow continued forward movement. Migration in OCs is regulated by two main pathways, αvβ3 integrin, which mediates

αvβ3 integrin: linking the OC to bone

Dynamic changes in the osteoclast cytoskeleton associated with the bone resorptive process are controlled by αvβ3 integrin (Faccio et al., 2003a). Deletion of β3 in mice leads to a progressive increase in bone mass, due to failure of resorption (McHugh et al., 2000). When differentiated in vitro, β3−/− osteoclasts do not spread or form a podosome belt when plated in physiological amounts of RANKL and M-CSF (Feng et al., 2001). Confirming their attenuated resorptive activity, β3−/− osteoclasts

αvβ3 integrin and OC motility

αvβ3 integrin localizes around the actin core of podosomes in the podosome belt of OCs plated on glass (Fig. 3, left). When OCs are stimulated to migrate with M-CSF, their cytoskeleton rapidly reorganizes. Podosome belts dissolve and αvβ3 moves to the leading edge of the lamellipodia (Fig. 3, right). In resorbing cells on bone, αvβ3 integrin is distributed along the inner and outer edge of the ring of actin forming the sealing zone. The cytoplasmic tail of the integrin receptor is required for

αvβ3 adhesion complex

Engagement of the αvβ3 integrin leads to remodeling of the actin cytoskeleton through the formation and activation of a large “adhesion complex”, containing enzymes, adaptors and scaffolding proteins. One major component of this complex in the OC is c-Src. c-Src knockout mice are severely osteopetrotic with OCs that fail to resorb bone (Soriano et al., 1991). In Src−/− OCs, the peripheral podosome belt is absent and replaced by irregular patches at the cell center, likely due to a decrease in

DAP12: a point of convergence between αvβ3 and M-CSF signaling pathways

DAP12, a transmembrane adapter molecule expressed in immune cells, is one common orchestrator of growth factor and integrin signals (Lanier and Bakker, 2000, Tomasello et al., 1998). In myeloid cells, DAP12 pairs with surface residing receptors including triggering receptor expressed on myeloid cells and osteoclasts (TREMs) (Colonna, 2003). The cytoplasmic domain of DAP12 contains the ITAM motif, which when phosphorylated functions as a docking site for tyrosine kinases, including Syk (McVicar

Downstream mediators of motility/cytoskeleton in the OC

The key effector for cytoskeletal rearrangement in OCs immediately downstream of Syk, and therefore M-CSF, αvβ3 integrin and DAP12, is Vav3. Syk activates Vav3 by direct phosphorylation. Vav3 null mice have increased bone mass due to decreased bone resorption by OCs (Faccio et al., 2005). In vitro, Vav3−/− OCs differentiate normally, but they fail to form podosome belts on glass or a sealing zone on bone, and have little resorptive activity.

Vav3 is a guanine nucleotide exchange factor (GEF) for

cdc42

cdc42 is another Rho family small GTPase which, when overexpressed as an activated mutant form in macrophages and OCs disrupts podosomes, depleting the core of F-actin (Chellaiah, 2005, Linder et al., 1999). However, more recent studies using mice with increased cdc42 activation due to knockout of its negative regulator cdc42GAP have shown increased sealing zone formation and bone resorption, compared to wildtype cells. Additionally, the formation of the Par3/Par6/aPKC polarity complex

RANKL and the OC cytoskeleton

In addition to its critical role in OC differentiation, RANKL has also been linked to control of the cytoskeleton. Addition of RANKL to mature OCs on bone enhances actin ring formation and bone resorption (Burgess et al., 1999). With RANKL stimulation of OCs expressing RANK mutants that are unable to interact with TRAF6, F-actin is found in clumps rather than rings, and c-src and c-cbl are mislocalized. As expected, bone resorption is impaired (Armstrong et al., 2002). Recently, a

Conclusion

The most common bone disease affecting the aging population is osteoporosis, a disease in which bone resorption exceeds formation. Because the OC is responsible for bone resorption, it has been the focus of anti-osteoporosis therapies, and the most commonly used class of drugs is the nitrogen-containing bisphosphonates. These drugs target FPP synthase, an enzyme in the cholesterol biosynthesis pathway required for the post-translational modification of small GTPases (including Rho, Rac, and

Acknowledgement

The authors wish to thank Paulette Shubert for assistance with figure and manuscript preparation, as well as support from the NIH, AR52921 (to RF) and AR052705 (to DVN), and the Children's Discovery Institute (MD-II-2009-179 to RF and DVN).

References (92)

A.P. Armstrong et al.
A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function
J. Biol. Chem.
(2002)
Y. Calle et al.
WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption
Blood
(2004)
M.A. Chellaiah
Regulation of actin ring formation by rho GTPases in osteoclasts
J. Biol. Chem.
(2005)
R. Chiusaroli et al.
Deletion of the gene encoding c-Cbl alters the ability of osteoclasts to migrate, delaying resorption and ossification of cartilage during the development of long bones
Dev. Biol.
(2003)
F.P. Coxon et al.
Vesicular trafficking in osteoclasts
Semin. Cell Dev. Biol.
(2008)
C.L. Elsegood et al.
M-CSF induces the stable interaction of cFms with alphaVbeta3 integrin in osteoclasts
Int. J. Biochem. Cell Biol.
(2006)
R. Faccio et al.
M-CSF regulates the cytoskeleton via recruitment of a multimeric signaling complex to c-Fms Tyr-Y559/697/721
J. Biol. Chem.
(2007)
S. Honda et al.
Topography of ligand-inducing binding sites, including a novel cation-sensitive epitope (AP5) at the amino terminus, of the human integrin β3 subunit
J. Biol. Chem.
(1995)
M.A. Horton et al.
Arg-gly-asp (RGD) peptides and the anti-vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts
Exp. Cell Res.
(1991)
N.P. Hunt et al.
The dental, craniofacial, and biochemical features of pyknodysostosis: a report of three new cases
J. Oral Maxillofac. Surg.
(1998)

Z. Jakus et al.

Immunoreceptor-like signaling by beta 2 and beta 3 integrins

Trends Cell Biol.

(2007)

G.E. Jones et al.

Restoration of podosomes and chemotaxis in Wiskott-Aldrich syndrome macrophages following induced expression of WASp

Int. J. Biochem. Cell Biol.

(2002)

G.E. Jones et al.

Requirement for PI 3-kinase [gamma] in macrophage migration to MCP-1 and CSF-1

Exp. Cell Res.

(2003)

P. Jurdic et al.

Podosome and sealing zone: specificity of the osteoclast model

Eur. J. Cell Biol.

(2006)

U. Kornak et al.

Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man

Cell

(2001)

D.L. Lacey et al.

Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation

Cell

(1998)

P.T. Lakkakorpi et al.

PYK2 autophosphorylation, but not kinase activity, is necessary for adhesion-induced association with c-Src, osteoclast spreading, and bone resorption

J. Biol. Chem.

(2003)

L.L. Lanier et al.

The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function

Immunol. Today

(2000)

S. Linder et al.

Podosomes: adhesion hot-spots of invasive cells

Trends Cell Biol.

(2003)

P.C. Marchisio et al.

Vinculin, talin, and integrins and localized at specific adhesion sites of malignant B lymphocytes

Blood

(1988)

D.W. McVicar et al.

DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase

J. Biol. Chem.

(1998)

F.J. Pixley et al.

CSF-1 regulation of the wandering macrophage: complexity in action

Trends Cell Biol.

(2004)

R. Rohatgi et al.

The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly

Cell

(1999)

F. Saltel et al.

Actin cytoskeletal organisation in osteoclasts: a model to decipher transmigration and matrix degradation

Eur. J. Cell Biol.

(2008)

P. Soriano et al.

Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice

Cell

(1991)

Y. Sun et al.

Possible role of direct Rac1–Rab7 interaction in ruffled border formation of osteoclasts

J. Biol. Chem.

(2005)

J. Takagi et al.

Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling

Cell

(2002)

E. Tomasello et al.

Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12

J. Biol. Chem.

(1998)

A. Zambonin-Zallone et al.

Immunocytochemical distribution of extracellular matrix receptors in human osteoclasts: a β3 integrin is colocalized with vinculin and talin in the podosomes of osteoclastoma giant cells

Exp. Cell Res.

(1989)

W. Zou et al.

DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk

Mol. Cell

(2008)

E.G. Arias-Salgado et al.

Src kinase activation by direct interaction with the integrin β cytoplasmic domain

Proc. Natl. Acad. Sci. USA

(2003)

D. Boettiger et al.

Activation of alpha(v)beta3-vitronectin binding is a multistage process in which increases in bond strength are dependent on Y747 and Y759 in the cytoplasmic domain of beta3

Mol. Biol. Cell

(2001)

T.L. Burgess et al.

The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts

J. Cell Biol.

(1999)

A. Chabadel et al.

CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts

Mol. Biol. Cell

(2007)

M. Colonna

TREMs in the immune system and beyond

Nat. Rev. Immunol.

(2003)

O. Destaing et al.

Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein

Mol. Biol. Cell

(2003)

O. Destaing et al.

A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts

J. Cell Sci.

(2005)

O. Destaing et al.

The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts

Mol. Biol. Cell

(2008)

H. Epple et al.

Phospholipase Cgamma2 modulates integrin signaling in the osteoclast by affecting the localization and activation of Src kinase

Mol. Cell. Biol.

(2008)

R. Faccio et al.

Localization and possible role of two different αvβ3 integrin conformations in resting and resorbing osteoclasts

J. Cell Sci.

(2002)

R. Faccio et al.

Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin

J. Cell Biol.

(2003)

R. Faccio et al.

High dose M-CSF partially rescues the Dap12−/− osteoclast phenotype

J. Cell. Biochem.

(2003)

R. Faccio et al.

Vav3 regulates osteoclast function and bone mass

Nat. Med.

(2005)

X. Feng et al.

A Glanzmann's mutation in β3 integrin specifically impairs osteoclast function

J. Clin. Invest.

(2001)

J.E. Fisher et al.

Inhibition of osteoclastic bone resorption in vivo by echistatin, an “arginyl-glycyl-aspartyl” (RGD)-containing protein

Endocrinology

(1993)

A. Frattini et al.

Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis

Nat. Genet.

(2000)

Cited by (68)

The role of integrin αvβ3 in biphasic calcium phosphate ceramics mediated M2 Macrophage polarization and the resultant osteoinduction
2024, Biomaterials
Calcium phosphate ceramics-based biomaterials were reported to have good biocompatibility and osteoinductivity and have been widely applied for bone defect repair and regeneration. However, the mechanism of their osteoinductivity is still unclear. In our study, we established an ectopic bone formation in vivo model and an in vitro macrophage cell co-culture system with calcium phosphate ceramics to investigate the effect of biphasic calcium phosphate on osteogenesis via regulating macrophage M1/M2 polarization. Our micro-CT data suggested that biphasic calcium phosphate had significant osteoinductivity, and the fluorescence co-localization detection found increased F4/80+/integrin αvβ3+ macrophages surrounding the biphasic calcium phosphate scaffolds. Besides, our study also revealed that biphasic calcium phosphate promoted M2 polarization of macrophages via upregulating integrin αvβ3 expression compared to tricalcium phosphate, and the increased M2 macrophages could subsequently augment the osteogenic differentiation of MSCs in a TGFβ mediated manner. In conclusion, we demonstrated that macrophages subjected to biphasic calcium phosphate could polarize toward M2 phenotype via triggering integrin αvβ3 and secrete TGFβ to increase the osteogenesis of MSCs, which subsequently enhances bone regeneration.
Versicotide G suppresses osteoclastogenesis and prevents osteolysis
2022, Bioorganic Chemistry
Excessive formation and function of osteoclasts cause various osteolytic bone diseases. Natural products are a potential source for the discovery of new therapeutic candidates to treat bone destruction diseases. In this study, chemical informatics and bioassay guided examination of the marine-derived Aspergillus versicolor F77 fungus chemically resulted in the isolation of seven cyclopeptides, of which versicotides G-J (1–4) are new cyclohexapeptides. Their structures were identified by spectroscopic data in association with Marfey method and single crystal X-ray diffraction data for configurational assignments. Bioassay revealed that versicotide G (1, VG) is the most active among the analogs to suppress the receptor activator of nuclear factor-KB ligand (RANKL)-induced osteoclastogenesis in bone marrow derived monocytes (BMMs) without affecting BMMs viability. VG also suppressed RANKL-induced actin-ring formation and resorbing function of osteoclast dose-dependently. Mechanistically, VG attenuated RANKL-induced intracellular calcium elevation by inhibiting PLCγ1 phosphorylation and blocking the activation of downstream phosphatase calcineurin. In addition, VG abrogated the expression and translocation of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), leading to the downregulation of the expression of osteoclast-specific genes and the abolishment of the osteoclast formation. In the in vivo test, VG suppressed osteoclast formation and bone loss in Ti-induced calvarial osteolytic mouse model.These findings imply that VG is a promising candidate for the remedy of bone destruction-related diseases.
Onc201 reduces osteoclastogenesis and prevents ovariectomy-induced bone loss via inhibiting RANKL-induced NFATc1 activation and the integrin signaling pathway
2022, European Journal of Pharmacology
Citation Excerpt :
The actin core is surrounded by adhesion-related proteins (including integrin, WASP interaction protein) and FAK family kinases, and is influenced by the c-Src kinase (Destaing et al., 2008; Linder and Aepfelbacher, 2003). Previous studies have indicated that both FAK and c-Src are induced by integrin αvβ3 in osteoclasts (Duong and Rodan, 1998; Xiong and Feng, 2003), and phosphorylated c-Src can further activate SYK, a non-receptor tyrosine kinase, leading to osteoclast cytoskeleton rearrangement and bone resorption (Novack and Faccio, 2011). Integrin αvβ3 recognizes proteins of the bone matrix, e.g., osteopontin and bone sialoprotein, through the extracellular domain, bringing the polarization of mature osteoclasts on the bone surface.
Osteoporosis is an osteolytic disease with a disrupted balance between the resorption and formation of bone as well as bone microstructure degeneration, leading to bone loss and increased fracture risk, which greatly affects patients’ quality of life. Currently, inhibition of osteoclast bone resorption remains the mainstream treatment for osteoporosis. Onc201, a new compound, induces the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and has an efficient anticancer effect in clinical trials. However, its effects on osteolytic disease and the mechanism of action are unclear. We examined the effect of Onc201 on nuclear factor κB ligand-receptor activator (RANKL)-induced osteoclasts via Cell Counting Kit-8, bone resorption assay, luciferase reporter assay, immunofluorescence staining, calcium ion intensity assay and employed an ovariectomy model to investigate the effect of Onc201 on osteoporosis in the mice. Results showed that Onc201 inhibited the function and formation of osteoclasts induced by RANKL in a manner that was dependent on time and concentration, and did not cause cytotoxicity. Mechanistically, Onc201 inhibited osteoclast-relevant genes and NFATc1 expression, the main transcriptional regulatory factor of the formation of osteoclasts induced by RANKL; meanwhile, downregulating the expressions of the osteoclast cytoskeleton key signal molecules integrin αvβ3, focal adhesion kinase (FAK), c-Src, and spleen-associated tyrosine kinase (SYK). In addition, Onc201 had a protective effect on the mouse model of bone loss caused by ovariectomy-induced estrogen deficiency, which is consistent with the in vitro results. Our findings suggest that the new small-molecular compound Onc201 has the potential to prevent osteoclast-related osteolytic diseases.
Cistanche deserticola polysaccharide inhibits OVX-induced bone loss in mice and RANKL-induced osteoclastogenesis
2021, Journal of Functional Foods
Osteoporosis is a serious bone disease affecting the aging population. Cistanche deserticola (CD), a tonic and medicinal food widely used in China, has been proved to provide effective treatment for osteoporosis. Cistanche deserticola polysaccharide (CDP), extracted from CD, possesses various pharmacological properties, but its role in osteoclastic formation and function as well as osteoporosis remains unknown. The purpose of this study was to extract and purify CDP to further explore its potential mechanism of action on osteoporosis. Results showed that the CDP treatment prevented OVX-induced osteoporosis and ameliorated bone loss by repressing osteoclast activity and function. Furthermore, CDP treatment significantly inhibited RANKL-induced osteoclastogenesis, bone resorption, and osteoclast-specific gene expression. Mechanistically, CDP inhibited RANKL-induced NF-κB and MAPKs signaling pathways activation and consequently affected the downstream NFATc1 activation. The findings in this study suggest that CDP is a potentially safe drug for treating osteoporosis.
Vitamin D receptor expression in mature osteoclasts reduces bone loss due to low dietary calcium intake in male mice
2021, Journal of Steroid Biochemistry and Molecular Biology
Mature osteoclasts express the vitamin D receptor (VDR) and are able to respond to active vitamin D (1α, 25-dihydroxyvitamin D₃; 1,25(OH)₂D₃) by regulating cell maturation and activity. However, the in vivo consequences of vitamin D signalling directly within functionally mature osteoclasts is only partially understood. To investigate the in vivo role of VDR in mature osteoclasts, conditional deletion of the VDR under control of the cathepsin K promoter (Ctsk^Cre/Vdr^−/−), was assessed in 6 and 12-week-old mice, either under normal dietary conditions (NormCaP) or when fed a low calcium (0.03 %), low phosphorous (0.08 %) diet (LowCaP). Splenocytes from Ctsk^Cre/Vdr^−/− mice were co-cultured with MLO-Y4 osteocyte-like cells to assess the effect on osteoclastogenesis. Six-week-old Ctsk^Cre/Vdr^-/- mice demonstrated a 10 % decrease in vertebral bone volume (p < 0.05), which was associated with increased osteoclast size (p < 0.05) when compared to Vdr^fl/fl control mice. Control mice fed a LowCaP diet exhibited extensive trabecular bone loss associated with increased osteoclast surface, number and size (p < 0.0001). Interestingly, Ctsk^Cre/Vdr^-/- mice fed a LowCaP diet showed exacerbated loss of bone volume fraction (BV/TV%) and trabecular number (Tb.N), by a further 22 % and 21 %, respectively (p < 0.05), suggesting increased osteoclastic bone resorption activity with the loss of VDR in mature osteoclasts under these conditions. Co-culture of Ctsk^Cre/Vdr^-/- splenocytes with MLO-Y4 cells increased resulting osteoclast numbers 2.5-fold, which were greater in nuclei density and exhibited increased resorption of dentine compared to osteoclasts derived from Vdr^fl/fl splenocyte cultures. These data suggest that in addition to RANKL-mediated osteoclastogenesis, intact VDR signalling is required for the direct regulation of the differentiation and activity of osteoclasts in both in vivo and ex vivo settings.
Osteoclast formation at the bone marrow/bone surface interface: Importance of structural elements, matrix, and intercellular communication
2021, Seminars in Cell and Developmental Biology
Citation Excerpt :
αVβ3 has been suggested to be particularly rich at podosomes in OCs. These are actin rich structures that make small protrusions of the cellular membrane ensuring a privileged contact to the bone matrix and in particular RGD-containing protein [105,110,111]. However, although the phenotype in vitro is severe, OCs deficient for β3 are not incapable of resorbing bone [109].
Osteoclasts, the multinucleated cells responsible for bone resorption, have an enormous destructive power which demands to be kept under tight control. Accordingly, the identification of molecular signals directing osteoclastogenesis and switching on their resorptive activity have received much attention. Mandatory factors were identified, but a very essential aspect of the control mechanism of osteoclastic resorption, i.e. its spatial control, remains poorly understood. Under physiological conditions, multinucleated osteoclasts are only detected on the bone surface, while their mono-nucleated precursors are only in the bone marrow. How are pre-osteoclasts targeted to the bone surface? How is their progressive differentiation coordinated with their approach to the bone surface sites to be resorbed, which is where they finally fuse? Here we review the information on the bone marrow distribution of differentiating pre-osteoclasts relative to the position of the mandatory factors for their differentiation as well as relative to physical entities that may affect their access to the remodelling sites. This info allows recognizing an “osteoclastogenesis route” through the bone marrow and leading to the coincident fusion/resorption site – but also points to what still remains to be clarified regarding this route and regarding the restriction of fusion at the resorption site. Finally, we discuss the mechanism responsible for the start of resorption and its spatial extension. This review underscores that fully understanding the control of bone resorption requires to consider it in both space and time - which demands taking into account the context of bone tissue.

View all citing articles on Scopus

View full text

ReviewOsteoclast motility: Putting the brakes on bone resorption

Abstract

Section snippets

Skeletal aging

OC differentiation

Resorptive machinery of an active OC

Podosomes: organizing principle of the OC cytoskeleton

M-CSF: a migratory stimulus and actin regulator

αvβ3 integrin: linking the OC to bone

αvβ3 integrin and OC motility

αvβ3 adhesion complex

DAP12: a point of convergence between αvβ3 and M-CSF signaling pathways

Downstream mediators of motility/cytoskeleton in the OC

cdc42

RANKL and the OC cytoskeleton

Conclusion

Acknowledgement

J. Biol. Chem.

Blood

J. Biol. Chem.

Dev. Biol.

Semin. Cell Dev. Biol.

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

J. Oral Maxillofac. Surg.

Trends Cell Biol.

Int. J. Biochem. Cell Biol.

Exp. Cell Res.

Eur. J. Cell Biol.

Cell

Cell

J. Biol. Chem.

Immunol. Today

Trends Cell Biol.

Blood

J. Biol. Chem.

Trends Cell Biol.

Cell

Eur. J. Cell Biol.

Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

Exp. Cell Res.

Mol. Cell

Src kinase activation by direct interaction with the integrin β cytoplasmic domain

Proc. Natl. Acad. Sci. USA

Activation of alpha(v)beta3-vitronectin binding is a multistage process in which increases in bond strength are dependent on Y747 and Y759 in the cytoplasmic domain of beta3

Mol. Biol. Cell

The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts

J. Cell Biol.

CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts

Mol. Biol. Cell

TREMs in the immune system and beyond

Nat. Rev. Immunol.

Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein

Mol. Biol. Cell

A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts

J. Cell Sci.

The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts

Mol. Biol. Cell

Phospholipase Cgamma2 modulates integrin signaling in the osteoclast by affecting the localization and activation of Src kinase

Mol. Cell. Biol.

Localization and possible role of two different αvβ3 integrin conformations in resting and resorbing osteoclasts

J. Cell Sci.

Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin

J. Cell Biol.

High dose M-CSF partially rescues the Dap12−/− osteoclast phenotype

J. Cell. Biochem.

Vav3 regulates osteoclast function and bone mass

Nat. Med.

A Glanzmann's mutation in β3 integrin specifically impairs osteoclast function

J. Clin. Invest.

Inhibition of osteoclastic bone resorption in vivo by echistatin, an “arginyl-glycyl-aspartyl” (RGD)-containing protein

Endocrinology

Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis

Nat. Genet.

Review
Osteoclast motility: Putting the brakes on bone resorption