The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo.
c-Src kinase is a rate-limiting activator of osteoclast (OC) function and Src inhibitors are therefore candidate antiosteoporosis drugs. By affecting alphavbeta3 and macrophage-colony stimulating factor (M-CSF)-induced signaling, c-Src is central to osteoclast activity, but not differentiation. We find Lyn, another member of Src family kinases (SFK) is, in contrast, a negative regulator of osteoclastic bone resorption. The absence of Lyn enhances receptor activator of NF-kappaB ligand (RANKL)-mediated differentiation of osteoclast precursors without affecting proliferation and survival, while its overexpression decreases osteoclast formation. In further contrast to c-Src, Lyn deficiency does not impact the activity of the mature cell. Reflecting increased osteoclast development in vitro, Lyn-/- mice undergo accelerated osteoclastogenesis and bone loss, in vivo, in response to RANKL. Mechanistically, Lyn forms a complex with receptor activator of NF-kappaB (RANK), the tyrosine phosphatase, SHP-1, and the adapter protein, Grb2-associated binder 2 (Gab2). Upon RANKL exposure, Gab2 phosphorylation, JNK, and NF-kappaB activation are enhanced in Lyn-/- osteoclasts, all critical events in osteoclast development. We therefore establish that Lyn regulates osteoclast formation and does it in a manner antithetical to that of c-Src. The most pragmatic aspect of our findings is that successful therapeutic inhibition of c-Src, in the context of the osteoclast, will require its stringent targeting.
Kim
Hyun-Ju
HJ
Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
Zhang
Kaihua
K
Zhang
Lihong
L
Ross
F Patrick
FP
Teitelbaum
Steven L
SL
Faccio
Roberta
R
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001862:Bone Resorption; D066298:In Vitro Techniques; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D016328:NF-kappa B; D010750:Phosphoproteins; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6