Osteoclastic bone resorption depends upon the cell's ability to organize its 
cytoskeleton via the αvβ3 integrin and osteoclastogenic cytokines. Because 
paxillin associates with αvβ3, we asked if it participates in skeletal 
degradation. Unlike deletion of other αvβ3-associated cytoskeleton-regulating 
molecules, which impairs the cell's ability to spread, paxillin-deficient 
(Pax(-/-) ) osteoclasts, generated from embryonic stem cells, "superspread" in 
response to receptor activator of NF-κB ligand (RANKL) and form large, albeit 
dynamically atypical, actin bands. Despite their increased size, Pax(-/-) 
osteoclasts resorb bone poorly, excavating pits approximately one-third normal 
depth. Ligand-occupied αvβ3 or RANKL promotes paxillin serine and tyrosine 
phosphorylation, the latter via cellular sarcoma (c-Src). The abnormal Pax(-/-) 
phenotype is rescued by wild-type (WT) paxillin but not that lacking its LD4 
domain. In keeping with the appearance of mutant osteoclasts, WT paxillin, 
overexpressed in WT cells, contracts the cytoskeleton. Most importantly, the 
abnormal phenotype of Pax(-/-) osteoclasts likely represents failed 
RANKL-mediated delivery of myosin IIA to the actin cytoskeleton via the paxillin 
LD4 domain but is independent of tyrosine phosphorylation. Thus, in response to 
RANKL, paxillin associates with myosin IIA to contract the osteoclast 
cytoskeleton, thereby promoting its bone-degrading capacity.