Osteoclasts lacking Rac2 have defective chemotaxis and resorptive activity.

Abstract

The role of the small Rho GTPase Rac2 in mature osteoclasts has not been extensively studied. Rac2(-/-) mice are of normal size and have normal tooth eruption. However, femoral cortical thickness was significantly greater in Rac2(-/-) compared to wild-type mice, while percent cortical porosity was lower. As assessed by histomorphometry, trabecular bone mass was significantly higher in male Rac2(-/-) than wild-type animals, although trabecular bone mass was similar when data from male and female animals were combined. There were no significant differences in the number of osteoblasts per bone surface; however, the number of osteoclasts per total bone area tended to be higher in Rac2(-/-) mice and was significantly higher in male Rac2(-/-) mice. In the aggregate, these data suggested a defect in osteoclast function and, consistent with that, rates of bone resorption were significantly reduced in Rac2(-/-) osteoclasts. In addition, Rac2(-/-) osteoclasts had a significantly delayed spreading response to treatment with CSF1 for 15 min. Phalloidin staining showed areas of abnormal actin accumulation and impaired actin ring formation in Rac2(-/-) osteoclasts. Finally, Rac2(-/-) osteoclasts showed a marked defect in chemotaxis toward a point source of CSF1, with a dramatic reduction in migratory rate. Together, these findings indicate an important role for Rac2 in mature osteoclasts.