Opposing roles of hematopoietic-specific small GTPase Rac2 and the guanine nucleotide exchange factor Vav1 in osteoclast differentiation

Vav1 regulates Rac activation as a hematopoietic-specific Rho/Rac-family guanine nucleotide exchange factor. Rac is a subfamily of Rho GTPases that regulates the bone-resorbing capacity of osteoclasts (OCs). In this study, we show that hematopoietic-specific Rac2 and Vav1 play opposing roles by enhancing or attenuating OC differentiation, respectively. This was demonstrated by higher and lower bone density in the femurs from Rac2-deficient (Rac2(−/−)) and Vav1-deficient (Vav1(−/−)) mice, respectively, compared to the wild-type (WT) mice. Accordingly, Rac2(−/−) cells displayed low numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (41%) compared to WT cells, whereas, Vav1(−/−) cells showed high TRAP-positive cell numbers (150%), and the double-knockout Rac2(−/−)Vav1(−/−) mice nullified the effects on OC numbers achieved by the individual knockouts. These reciprocal roles of Rac2 and Vav1 in OC differentiation were confirmed by reduced and increased levels of OC-specific markers, such as TRAP, calcitonin receptor, cathepsin K, and DC-STAMP in the Rac2(−/−) and Vav1(−/−) OCs, respectively. Our findings of decrease and increase in actin ring formation and α(v)β(3) integrin-mediated adhesion in Rac2(−/−) and Vav1(−/−) mice, respectively, suggest that Vav1 and its downstream GTPase, Rac2, may counteract to fine-tune OC differentiation and bone resorption.