Figure 2: Roles of small GTPases in regulating the cytoskeleton. Rho activity is high in osteoclast precursors and promotes polarization. Rho decreases microtubule stability through activation of mDia/HDAC6 leading to osteoclast retraction. Rap1 promotes the inside-out activation of integrin, causing enhanced affinity for RGD ligand. Affinity for RGD is negatively regulated by Wrch1/RhoU in osteoclast precursors. Rac mediates M-CSF induced osteoclast spreading. Rac and Cdc42 promote actin polymerization and sealing zone formation, which is critical to osteoclast resorption. Arf6 negatively regulates the sealing zone in mature osteoclasts.