Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements.

Podosomes are recently rediscovered highly dynamic actin-rich structural and functional modules that form close contact with the surrounding substrate. They play a role in the control of migration, tissue invasion, and matrix remodeling of highly motile cells, including lymphocytes, macrophages, dendritic cells, and osteoclasts. In osteoclasts, the compaction of podosomes induces the formation of a tight adhesive contact, the sealing zone, which defines a subosteoclastic environment specialized for bone resorption. Integrins and the Rho family small GTPases are key regulators of podosome rearrangements. However, it remains to be determined how the activation of integrins and Rho family GTPases is regulated during osteoclast podosome rearrangements. Here, we demonstrate a crucial role for the FERM domain-containing guanine nucleotide exchange factor (GEF), FARP2, in osteoclast podosome rearrangements and resorbing activity. We determine by live cell imaging and biochemical assays that FARP2 is required for localized activation of GTP-bound Rac1 into podosome-ring like structures. In addition, FARP2 is relevant to integrin β3 activity during osteoclastogenesis. Furthermore, FARP2 deficiency results in reduced formation of multinucleated osteoclasts and resorption pits compared to wild-type osteoclasts (controls). Collectively, our findings reveal an integral role of FARP2 for regulation of Rac1 and integrin β3 throughout podosome rearrangement in osteoclastogenesis.