Rac deletion in osteoclasts causes severe osteopetrosis
Year: 2011
Type: article
Abstract: Cdc42 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(-/-) 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.
Source: Journal of Cell Science
DOI: 10.1242/jcs.086280
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G151374072, G1623190254, G1848037744, Mechanisms of AVB3 Integrin Mediated Bone Resorption, G35768402, G3606061126, Core Center for Musculoskeletal Biology and Medicine, G4606929459, G4618144033, G4742556320, G500294632, G5374603982, M-CSF Signaling in Osteoclast Formation and Function, G5878414408, G6440500099, CDC 42 BIM AND THE OSTEOCLAST, G6992116998, G75640898, Washington University Nutrition Obesity Research Center
OpenAlex ID: W2010806001