Gab2 plays distinct roles in bone homeostasis at different time points.

Grb2-associated binder 2 (Gab2) is an adaptor molecule that can be tyrosine phosphorylated by various growth factors and cytokines. Gab2 is known to play a role in signaling pathways downstream of cytokines that regulate bone homeostasis, including M-CSF, RANKL, and IL-6. To clarify the role of Gab2 in bone homeostasis during distinct phases of skeletal development, we compared phenotypic changes in bone homeostasis in Gab2(-/-) mice at two different ages. Although Gab2(-/-) mice showed increased bone volume at both time points, the reasons underlying the increased bone volume differed. At 6 weeks, the increased bone volume was due to enhanced bone resorption and bone formation, indicating that Gab2 plays a negative regulatory role for both osteoclastogenesis and osteoblast differentiation. At 12 weeks, the increased bone volume resulted from reduced osteoclast differentiation, indicating that Gab2 plays a positive regulatory role for osteoclastogenesis. Thus, Gab2 plays opposite roles in osteoclastogenesis during the phases of skeletal development and maintenance.