Regulation of Osteoclast Apoptosis and Motility by Small GTPase Binding Protein Rac1

Fukuda, Akira; Hikita, Atsuhiko; Wakeyama, Hidetoshi; Akiyama, Tsuyoshi; Oda, Hiromi; Nakamura, Kozo; Tanaka, Sakae

doi:10.1359/jbmr.050816

Cited by 73 publications

(57 citation statements)

References 45 publications

(55 reference statements)

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“…The fact that, unlike osteoclasts lacking Cdc42, LysMRacDKO osteoclasts are abundant in vivo, buttresses the conclusion that differentiation of the cell is not altered. Furthermore, in keeping with the observations of Fukuda et al, Rac suppression in osteoclastic cells promotes apoptosis (Fukuda et al, 2005). Although the mechanism of this event is yet to be determined, it might represent compromised binding of the avb3 integrin to its immobilized ligand, which promotes programmed death of the bone resorptive cell (Fukuda et al, 2005;Zhao et al, 2005).…”

Section: Discussionsupporting

confidence: 62%

Rac deletion in osteoclasts causes severe osteopetrosis

Croke

Ross

Korhonen

et al. 2011

Journal of Cell Science

106

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SummaryCdc42 mediates bone resorption principally by stimulating osteoclastogenesis. Whether its sister GTPase, Rac, meaningfully impacts upon the osteoclast and, if so, by what means, is unclear. We find that whereas deletion of Rac1 or Rac2 alone has no effect, variable reduction of Rac1 in osteoclastic cells of Rac2 2/2 mice causes severe osteopetrosis. Osteoclasts lacking Rac1 and Rac2 in combination (Rac double-knockout, RacDKO), fail to effectively resorb bone. By contrast, osteoclasts are abundant in RacDKO osteopetrotic mice and, unlike those deficient in Cdc42, express the maturation markers of the cells normally. Hence, the osteopetrotic lesion of RacDKO mice largely reflects impaired function, and not arrested differentiation, of the resorptive polykaryon. The dysfunction of RacDKO osteoclasts represents failed cytoskeleton organization as evidenced by reduced motility of the cells and their inability to spread or generate the key resorptive organelles (i.e. actin rings and ruffled borders), which is accompanied by abnormal Arp3 distribution. The cytoskeleton-organizing capacity of Rac1 is mediated through its 20-amino-acid effector domain. Thus, Rac1 and Rac2 are mutually compensatory. Unlike Cdc42 deficiency, their combined absence does not impact upon differentiation but promotes severe osteopetrosis by dysregulating the osteoclast cytoskeleton.

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Section: Discussionsupporting

confidence: 62%

Rac deletion in osteoclasts causes severe osteopetrosis

Croke

Ross

Korhonen

et al. 2011

Journal of Cell Science

106

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“…The activity of Rho GTPases is tightly regulated in osteoclasts, and increasing or decreasing either Rac or RhoA activity is equally deleterious on the podosome belt (Ory et al, 2000), whereas dissolution of the podosome belt upon osteoclast migration is accompanied by increased activity of Rac and RhoA (Fukuda et al, 2005;Kim et al, 2006;Sakai et al, 2006). We found that tensin 3 siRNA strongly increased the global activity of RhoA (Fig.…”

Section: Tensin 3 Stimulates Dock5 Exchange Activity Towards Racmentioning

confidence: 53%

Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity

Touaitahuata

Morel

Urbach

et al. 2016

Journal of Cell Science

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Bone resorption by osteoclasts is mediated by a typical adhesion structure called the sealing zone or actin ring, whose architecture is based on a belt of podosomes. The molecular mechanisms driving podosome organization into superstructures remain poorly understood to date, in particular at the osteoclast podosome belt. We performed proteomic analyses in osteoclasts and found that the adaptor protein tensin 3 is a partner of Dock5, a Rac exchange factor necessary for podosome belt formation and bone resorption. Expression of tensin 3 and Dock5 concomitantly increase during osteoclast differentiation. These proteins associate with the osteoclast podosome belt but not with individual podosomes, in contrast to vinculin. Super-resolution microscopy revealed that, even if they colocalize in the x-y plane of the podosome belt, Dock5 and tensin 3 differentially localize relative to vinculin in the z-axis. Tensin 3 increases Dock5 exchange activity towards Rac, and suppression of tensin 3 in osteoclasts destabilizes podosome organization, leading to delocalization of Dock5 and a severe reduction in osteoclast activity. Our results suggest that Dock5 and tensin 3 cooperate for osteoclast activity, to ensure the correct organization of podosomes.

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“…The migration of osteoclasts is enhanced in a Gidependent manner (49). Rac1 is generally thought to play a role in cell motility (33) and was indeed reported to be involved in the motility of osteoclasts (48,50). The functional cycle of bone resorption by osteoclasts consists of bone adherence, bone degradation, bone detachment, and movement to a new site of resorption (35,54).…”

Section: Discussionmentioning

confidence: 99%

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

Hikiji

Ishii

Yokomizo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Although leukotriene B4 (LTB4) is produced in various inflammatory diseases, its functions in bone metabolism remain unknown. Using mice deficient in the high-affinity LTB4 receptor BLT1, we evaluated the roles of BLT1 in the development of two bone resorption models, namely bone loss induced by ovariectomy and lipopolysaccharide. Through observations of bone mineral contents and bone morphometric parameters, we found that bone resorption in both models was significantly attenuated in BLT1-deficient mice. Furthermore, osteoclasts from BLT1-deficient mice showed reduced calcium resorption activities compared with wild-type osteoclasts. Osteoclasts expressed BLT1, but not the low-affinity LTB4 receptor BLT2, and produced LTB4. LTB4 changed the cell morphology of osteoclasts through the BLT1-Gi protein-Rac1 signaling pathway. Given the causal relationship between osteoclast morphology and osteoclastic activity, these findings suggest that autocrine/paracrine LTB4 increases the osteoclastic activity through the BLT1-Gi protein-Rac1 signaling pathway. Inhibition of BLT1 functions may represent a strategy for preventing bone resorption diseases.bone remodeling ͉ G protein-coupled receptor ͉ knockout mice ͉ lipid mediator ͉ osteoporosis ͉ L eukotriene B 4 (LTB 4 ), a metabolite of arachidonic acid, is a potent lipid mediator with various biological activities toward neutrophils and differentiated T cells, including chemotaxis, degranulation, and production of superoxide anions (1, 2). These actions of LTB 4 are mediated by specific cell surface receptors (BLTs). We previously cloned two distinct BLTs, BLT1 and BLT2 (3,4). BLT1 is a high-affinity receptor that mediates the inhibition of adenylate cyclase and calcium entry by coupling with the Gi-and Gq-classes of G proteins (5). BLT2 transduces comparable intracellular signals but has a lower affinity to LTB 4 (5). Although several hydroxyeicosatetraenoic acids were found to activate BLT2 (6), we recently identified 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT) as a very potent endogenous ligand for BLT2 (7). LTB 4 is produced in inf lammatory diseases such as psoriasis (8), bronchial asthma (9), ulcerative colitis (10), postischemic tissue injuries (11), and rheumatoid arthritis (12-15).Bone remodeling consists of old bone resorption by osteoclasts and new bone deposition by osteoblasts. Osteoclasts and osteoblasts participate in bone remodeling under the control of many hormones, cytokines (16,17), and autacoids, including lipid mediators (18). The effects of LTB 4 on bone resorption were investigated using organ cultures of mouse calvariae (19,20). LTB 4 enhanced calcium efflux from the mouse calvariae, suggesting that LTB 4 stimulates bone resorption (19). LTB 4 increased the formation of resorption pits by osteoclasts in rat bone tissues (20), suggesting that LTB 4 modulates bone resorption by increasing the number and/or activity of osteoclasts. However, few reports have provided definitive biochemical information about the mRNA/protein expression and ...

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Regulation of Osteoclast Apoptosis and Motility by Small GTPase Binding Protein Rac1

Cited by 73 publications

References 45 publications

Rac deletion in osteoclasts causes severe osteopetrosis

Rac deletion in osteoclasts causes severe osteopetrosis

Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

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Regulation of Osteoclast Apoptosis and Motility by Small GTPase Binding Protein Rac1

Cited by 73 publications

References 45 publications

Rac deletion in osteoclasts causes severe osteopetrosis

Rac deletion in osteoclasts causes severe osteopetrosis

Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity

A distinctive role of the leukotriene B 4 receptor BLT1 in osteoclastic activity during bone loss

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A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss