Paxillin contracts the osteoclast cytoskeleton.
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.
Department of Pathology and Immunology, School of Medicine, Washington University, St. Louis, MO 63110, USA.
Wei
W
Zou
Carl J
CJ
Deselm
Thomas J
TJ
Broekelmann
Robert P
RP
Mecham
Scott
S
Vande Pol
Kyunghee
K
Choi
Steven L
SL
Teitelbaum
D000818:Animals; D001862:Bone Resorption / Q000503:physiopathology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D051419:Paxillin / Q000494:pharmacology*; D010766:Phosphorylation; D053245:RANK Ligand / Q000502:physiology
D039302:Integrin alphaVbeta3; D051419:Paxillin; D053245:RANK Ligand; D024507:Nonmuscle Myosin Type IIA