Tomohiro Fukunaga, Wei Zou, Julia T. Warren and Steven L. Teitelbaum
Osteoclastic bone resorption depends upon the cell's ability to organize its cytoskeleton. Because vinculin (VCL) is an actin-binding protein, we asked if it participates in skeletal degradation. Thus, we mated VCLfl/fl mice with those expressing cathepsin K-Cre (CtsK-VCL) to delete the gene in mature osteoclasts or lysozyme M-Cre (LysM-VCL) to target all osteoclast lineage cells. VCL-deficient osteoclasts differentiate normally but reflecting cytoskeletal disorganization, form small actin-rings and fail to effectively resorb bone. In keeping with inhibited resorptive function, CtsK-VCL and LysM-VCL mice exhibit a doubling of bone mass. Despite cytoskeletal disorganization, the capacity of VCL-/- osteoclastic cells to normally phosphorylate c-Src in response to αvβ3 integrin ligand is intact. Thus, integrin activated signals are unrelated to the means by which VCL organizes the osteoclast cytoskeleton. WT VCL completely rescues actin-ring formation and bone resorption as does VCLP878A which is incapable of interacting with Arp2/3. As expected, deletion of the VCL tail domain (VCL1-880) which binds actin, does not normalize VCL-/- osteoclasts. The same holds regarding VCLA50I and VCL 811-1066 both of which arrest talin association. Thus, VCL binding talin, but not Arp2/3, is critical for osteoclast function and its selective inhibition retards physiological bone loss.