1. The immunomodulatory adapter proteins DAP12 and Fc receptor [gamma]-chain (FcR[gamma]) regulate development of functional osteoclasts through the Syk tyrosine kinase
- Author
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Mocsai, Attila, Humphrey, Mary Beth, Van Ziffle, Jessica A.G., Hu, Yongmei, Burghardt, Andrew, Spusta, Steven C., Majumdar, Sharmila, Lanier, Lewis L., Lowell, Clifford A., and Nakamura, Mary C.
- Subjects
Proteins -- Research ,Science and technology - Abstract
Osteoclasts, the only bone-resorbing cells, are central to the pathogenesis of osteoporosis, yet their development and regulation are incompletely understood. Multiple receptors of the immune system use a common signaling paradigm whereby phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) within receptor-associated adapter proteins recruit the Syk tyrosine kinase. Here we demonstrate that a similar mechanism is required for development of functional osteoclasts. Mice lacking two ITAM-bearing adapters, DAP12 and the Fc receptor [gamma]-chain (FcR[gamma]), are severely osteopetrotic. [DAP12.sup-/-][FcR[gamma].sup.-/-] bone marrow cells fail to differentiate into multinucleated osteoclasts or resorb bone in vitro and show impaired phosphorylation of the Syk tyrosine kinase, [syk.sup.-/-] progenitors are similarly defective in osteoclast development and bone resorption. Intact SH2-domains of Syk, introduced by retroviral transduction, are required for functional reconstitution of [syk.sup.-/-] osteoclasts, whereas intact ITAM-domains on DAP12 are required for reconstitution of [DAP12.sup.-/-][FcR[gamma].sup.-/-] cells. These data indicate that recruitment of Syk to phosphorylated ITAMs is critical for osteodastogenesis. Although DAP12 appears to be primarily responsible for osteoclast differentiation in cultures directly stimulated with macrophage-colony stimulating factor and receptor activator of NF-[kappa]B ligand cytokines, DAP12 and FcR[gamma] have overlapping roles in supporting osteoclast development in osteoblast-osteoclast cocultures, which mirrors their overlapping functions in vivo. These results provide new insight into the biology of osteoclasts and suggest novel therapeutic targets in diseases of bony remodeling.
- Published
- 2004