c-Src Links a RANK/<i>α</i>vβ3 Integrin Complex to the Osteoclast Cytoskeleton

Izawa, Takashi; Zou, Wei; Chappel, Jean; Ashley, Jason W.; Xu, Feng; Teitelbaum, Steven L.

doi:10.1128/mcb.00077-12

Cited by 59 publications

(60 citation statements)

References 31 publications

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“…As others have shown (Izawa et al, 2012), bone adherent and transduced mBMMs differentiated into mature OCLs after 8 days of RANKL treatment. Although cells seeded on bone slices had significantly diminished motility compared to cells tracked on plastic, the pattern of stimulation with RANKL and the significant dominant suppression by ActA was sustained.…”

Section: Discussionsupporting

confidence: 62%

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Fowler

Kamalakar

Akel

et al. 2015

Journal of Cell Science

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BSTRACTThe process of osteoclastic bone resorption is complex and regulated at multiple levels. The role of osteoclast (OCL) fusion and motility in bone resorption are unclear, with the movement of OCL on bone largely unexplored. RANKL (also known as TNFSF11) is a potent stimulator of murine osteoclastogenesis, and activin A (ActA) enhances that stimulation in whole bone marrow. ActA treatment does not induce osteoclastogenesis in stroma-free murine bone marrow macrophage cultures (BMM), but rather inhibits RANKL-induced osteoclastogenesis. We hypothesized that ActA and RANKL differentially regulate osteoclastogenesis by modulating OCL precursors and mature OCL migration. Time-lapse video microscopy measured ActA and RANKL effects on BMM and OCL motility and function. ActA completely inhibited RANKLstimulated OCL motility, differentiation and bone resorption, through a mechanism mediated by ActA-dependent changes in SMAD2, AKT1 and inhibitor of nuclear factor kB (IkB) signaling. The potent and dominant inhibitory effect of ActA was associated with decreased OCL lifespan because ActA significantly increased activated caspase-3 in mature OCL and OCL precursors.Collectively, these data demonstrate a dual action for ActA on murine OCLs.

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Section: Discussionsupporting

confidence: 62%

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Fowler

Kamalakar

Akel

et al. 2015

Journal of Cell Science

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“…SFK phosphorylation at Tyr-418 is known to occur during integrin ligation [28] and following force activation [17,29]; surprisingly, in mdMSCs mechanical strain did not induce phosphorylation at this site following strain durations of 2–30 minutes (10 cycles per minute) (Fig. 3C, showing 100 cycles of strain).…”

Section: Resultsmentioning

confidence: 96%

Mechanically activated fyn utilizes mTORC2 to regulate RhoA and adipogenesis in mesenchymal stem cells

et al. 2013

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Mechanical strain provides an anti-adipogenic, pro-osteogenic stimulus to mesenchymal stem cells (MSC) through generating intracellular signals and via cytoskeletal restructuring. Recently, mTORC2 has been shown to be a novel mechanical target critical for the anti-adipogenic signal leading to preservation of β-catenin. As mechanical activation of mTORC2 requires focal adhesions (FAs), we asked whether proximal signaling involved Src and FAK, which are early responders to integrin-FA engagement. Application of mechanical strain to marrow-derived MSCs was unable to activate mTORC2 when Src family kinases were inhibited. Fyn, but not Src, was specifically required for mechanical activation of mTORC2 and was recruited to FAs after strain. Activation of mTORC2 was further diminished following FAK inhibition, and as FAK phosphorylation (Tyr-397) required Fyn activity, provided evidence of Fyn/FAK cooperativity. Inhibition of Fyn also prevented mechanical activation of RhoA as well as mechanically induced actin stress fiber formation. We thus asked whether RhoA activation by strain was dependent on mTORC2 downstream of Fyn. Inhibition of mTORC2 or its downstream substrate, Akt, both prevented mechanical RhoA activation, indicating that Fyn/FAK affects cytoskeletal structure via mTORC2. We then sought to ascertain whether this Fyn-initiated signal pathway modulated MSC lineage decisions. siRNA knockdown of Fyn, but not Src, led to rapid attainment of adipogenic phenotype with significant increases in adipocyte protein 2, peroxisome proliferator-activated receptor gamma, adiponectin, and perilipin. As such, Fyn expression in mdMSCs contributes to basal cytoskeletal architecture and, when associated with FAs, functions as a proximal mechanical effector for environmental signals that influence MSC lineage allocation.

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“…Such being the case, activated RANK should rescue the ASXL2−/− osteoclast phenotype. To confirm this notion, we expressed a protein consisting of the transmembrane and cytosolic domains of RANK fused to the external domain of human Fas receptor (hFas/RANK) (Izawa et al, 2012). When exposed to anti-hFas antibody, WT macrophages bearing this construct differentiate into osteoclasts (Fig 3H).…”

Section: Resultsmentioning

confidence: 99%

ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis

et al. 2015

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Summary ASXL2 is an ETP family protein that interacts with PPARγ. We find that ASXL2−/− mice are insulin resistant, lipodystrophic and fail to respond to a high fat diet. Consistent with genetic variation at the ASXL2 locus and human bone mineral density, ASXL2−/− mice are also severely osteopetrotic due to failed osteoclast differentiation attended by normal bone formation. ASXL2 regulates the osteoclast via two distinct signaling pathways. It induces osteoclast formation in a PPARγ/c-Fos-dependent manner and is required for RANK ligand- and thiazolidinedione-induced bone resorption, independent of PGC-1β. ASXL2 also promotes osteoclast mitochondrial biogenesis in a process mediated by PGC-1β but independent of c-Fos. Thus, ASXL2 is a master regulator of skeletal, lipid and glucose homeostasis.

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c-Src Links a RANK/αvβ3 Integrin Complex to the Osteoclast Cytoskeleton

Cited by 59 publications

References 31 publications

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Mechanically activated fyn utilizes mTORC2 to regulate RhoA and adipogenesis in mesenchymal stem cells

ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis

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