Regulation of bone mass and osteoclast function depend on the F-actin modulator SWAP-70

Garbe, Annette I.; Roscher, Anne; Schüler, Christiane; Lutter, Anne-Helen; Glösmann, Martin; Bernhardt, Ricardo; Chopin, Michaël; Hempel, Ute; Hofbauer, Lorenz C.; Rammelt, Stefan; Egerbacher, Monika; Erben, Reinhold G.; Jessberger, Rolf

doi:10.1002/jbmr.1670

Cited by 43 publications

(52 citation statements)

References 55 publications

(64 reference statements)

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“…Interestingly, however, Def6 and Swap70 play different roles in osteoclast biology although they are highly homologous in sequences and structural domain arrangement. Swap70 does not significantly affect the differentiation of osteoclasts, but was found by Jessberger group (39) and also our group (unpublished data) to promote osteoclast resorptive function by regulating F-actin rearrangement. In this study, we revealed the inhibitory role of Def6 in osteoclast differentiation.…”

Section: Discussionmentioning

confidence: 54%

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Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

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Miller

Yoshida

et al. 2017

The Journal of Immunology

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Inflammatory bone resorption mediated by osteoclasts is a major cause of morbidity and disability in many inflammatory disorders, including rheumatoid arthritis (RA). The mechanisms that regulate osteoclastogenesis and bone resorption in inflammatory settings are complex and have not been well elucidated. In this study, we identify the immunoregulator Def6 as a novel inhibitor of osteoclastogenesis in both physiological and inflammatory conditions. Def6 deficiency in Def6−/− mice enhanced the sensitivity of osteoclast precursors to the physiological osteoclastogenic inducer RANKL, and Def6−/− osteoclasts formed actin rings. Furthermore, Def6 deficiency markedly increased TNF-α-induced osteoclastogenesis both in vitro and in vivo and enhanced bone resorption in an inflammatory osteolysis mouse model. TNF-α serum levels negatively correlated with Def6 expression levels in osteoclast precursors obtained from RA patients and the osteoclastogenic capacity of the osteoclast precursors was significantly inversely correlated with their Def6 expression levels, indicating that Def6 functions as an inhibitor of excessive osteoclast formation and bone destruction in RA. Mechanistically, Def6 suppressed osteoclastogenesis and the expression of key osteoclastogenic factors NFATc1, Blimp1 and c-Fos by regulating an endogenous IFN-β mediated autocrine feedback loop. The Def6-dependent pathway may represent a novel therapeutic target to prevent pathological bone destruction.

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Section: Discussionmentioning

confidence: 54%

“…Swap-70 plays various roles in different cell types. In bone biology, SWAP-70 regulates osteoclast function but not differentiation (39). Previous studies show that Def6 is also expressed in myeloid cells and regulates innate immunity (40).…”

Section: Introductionmentioning

confidence: 99%

Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

Binder

Miller

Yoshida

et al. 2017

The Journal of Immunology

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“…SWAP70 is expressed in many cell types, including mast cells (Gross et al., 2002), fibroblasts (Shinohara et al., 2002), dendritic cells (Oberbanscheidt et al., 2007), monocytes, and macrophages (Hilpelä et al., 2003). In these cells, the absence of SWAP70 leads to defects in actin polymerization and impairs cell migration, adhesion, polarization, and morphology (Bahaie et al., 2012, Chopin et al., 2010, Garbe et al., 2012, Murugan et al., 2008, Ocaña-Morgner et al., 2011, Pearce et al., 2006, Ripich and Jessberger, 2011, Shinohara et al., 2002, Sivalenka and Jessberger, 2004). SWAP70 can directly bind, bundle, and stabilize actin filaments by means of its C-terminal actin binding domain (Chacón-Martínez et al., 2013, Gomez-Cambronero, 2012, Hilpelä et al., 2003, Ihara et al., 2006, Murugan et al., 2008, Pearce et al., 2011, Shinohara et al., 2002).…”

Section: Introductionmentioning

confidence: 99%

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis

et al. 2016

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SummaryActin plays a critical role during the early stages of pathogenic microbe internalization by immune cells. In this study, we identified a key mechanism of actin filament tethering and stabilization to the surface of phagosomes in human dendritic cells. We found that the actin-binding protein SWAP70 is specifically recruited to nascent phagosomes by binding to the lipid phosphatidylinositol (3,4)-bisphosphate. Multi-color super-resolution stimulated emission depletion (STED) microscopy revealed that the actin cage surrounding early phagosomes is formed by multiple concentric rings containing SWAP70. SWAP70 colocalized with and stimulated activation of RAC1, a known activator of actin polymerization, on phagosomes. Genetic ablation of SWAP70 impaired actin polymerization around phagosomes and resulted in a phagocytic defect. These data show a key role for SWAP70 as a scaffold for tethering the peripheral actin cage to phagosomes.

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“…The prominent reduction of the CD3+ T cell population within the bone marrow of the mutant mice could be a result of intrinsic T cell defects. It is less likely to be an effect of the altered bone marrow environment, which is osteopetrotic only in Swap-70 -/- mice [22]. In contrast to SWAP-70, DEF6 is expressed in thymocytes and peripheral T cells and has been shown to be an important regulator of T cell development and homeostasis [4, 5, 23].…”

Section: Resultsmentioning

confidence: 99%

“…Since both proteins are expressed in a variety of hematopoietic cell types, and since Swap-70 -/- but not Def6 -/- mice develop mild osteopetrosis [22], some of the variations and age-dependent compensatory mechanisms described above may have been generated through interactions of the HSPCs with the mutant bone and marrow environment. Therefore we asked whether the role of SWAP-70 and DEF6 in HSC maintenance and differentiation is intrinsic to these cells.…”

Section: Resultsmentioning

confidence: 99%

SWEF Proteins Distinctly Control Maintenance and Differentiation of Hematopoietic Stem Cells

et al. 2016

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SWAP-70 and DEF6, two proteins that feature similar domain and motif arrangements, are mainly known for their functions in differentiated hematopoietic cells. Both proteins interact with and regulate RhoGTPases and F-actin dynamics, yet their role in hematopoietic stem and precursor cells (HSPCs) remained unexplored. Here, the role of the SWEF proteins SWAP-70 and DEF6 in HSPCs was examined. Both SWEF proteins are expressed in HSCs. HSCs and different precursor populations were analyzed in mice deficient for SWAP-70, DEF6, SWAP-70 and DEF6 (double knockout, DKO), and wild-type controls. HSPCs isolated from these strains were used for competitive adoptive transfer into irradiated wild-type mice. Reconstitution of the myeloid and lymphoid lineages in the recipient mice was determined. The numbers of HSPCs in the bone marrow of Swap-70-/- and Swap-70-/-Def6-/- mice were >3-fold increased. When transplanted into lethally irradiated wild-type recipients, the reconstitution potential of Swap-70-/- HSPCs was intrinsically impaired in competing with wild-type HSPCs for contribution to hematopoiesis. Def6-/- HSPCs show wild type-like reconstitution potential under the same transplantation conditions. DKO HSPCs reconstituted to only 25% of wild-type levels, indicating a partial rescue by DEF6 deficiency in the Swap-70-/- background. Our study reveals the two SWEF proteins as important contributors to HSPC biology. Despite their similarity these two proteins regulate HSC/progenitor homeostasis, self-renewal, lineage contributions and repopulation in a distinct and mostly antagonistic manner.

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Regulation of bone mass and osteoclast function depend on the F-actin modulator SWAP-70

Cited by 43 publications

References 55 publications

Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis

SWEF Proteins Distinctly Control Maintenance and Differentiation of Hematopoietic Stem Cells

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