The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase
Attila Mócsai,Mary Beth Humphrey,Jessica Van Ziffle,Yongmei Hu,Andrew J. Burghardt,Steven C. Spusta,Sharmila Majumdar,Lewis L. Lanier,Clifford A. Lowell,Mary C. Nakamura +9 more
TLDR
Data indicate that recruitment of Syk to phosphorylated ITAMs is critical for osteoclastogenesis, which provides new insight into the biology of osteoclasts and suggest novel therapeutic targets in diseases of bony remodeling.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 (FcRgamma), are severely osteopetrotic. DAP12(-/-)FcRgamma(-/-) bone marrow cells fail to differentiate into multinucleated osteoclasts or resorb bone in vitro and show impaired phosphorylation of the Syk tyrosine kinase. syk(-/-) 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(-/-) osteoclasts, whereas intact ITAM-domains on DAP12 are required for reconstitution of DAP12(-/-) FcRgamma(-/-) cells. These data indicate that recruitment of Syk to phosphorylated ITAMs is critical for osteoclastogenesis. Although DAP12 appears to be primarily responsible for osteoclast differentiation in cultures directly stimulated with macrophage-colony stimulating factor and receptor activator of NF-kappaB ligand cytokines, DAP12 and FcRgamma 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.read more
Citations
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Journal ArticleDOI
Nk cell recognition
TL;DR: The structure, function, and ligand specificity of the receptors responsible for NK cell recognition are reviewed and the role of EMT inNK cell recognition is reviewed.
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Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems
TL;DR: The two systems should be understood to be integrated and operating in the context of the 'osteoimmune' system, a heuristic concept that provides not only a framework for obtaining new insights by basic research, but also a scientific basis for the discovery of novel treatments for diseases related to both systems.
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The molecular understanding of osteoclast differentiation.
TL;DR: The RANKL signaling pathway has promise as a strategy for suppressing the excessive osteoclast formation characteristic of a variety of bone diseases and is controlled by an epigenetic mechanism, which has profound implications for the general mechanism of irreversible cell fate determination.
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The SYK tyrosine kinase: a crucial player in diverse biological functions.
TL;DR: Current understanding of the diverse functions of SYK is summarized and how this is being translated for therapeutic purposes is summarized.
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Skeletal remodeling in health and disease.
TL;DR: This review summarizes the current understanding of the carefully orchestrated cross-talk between cells of the bone marrow and between bone cells and the brain through which bone is constantly remodeled during adult life and highlights molecular aberrations that cause bone cells to become dysfunctional.
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