title: The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase.
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.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Humphrey
authors.forename: Jessica A G
authors.initials: JA
authors.lastname: Van Ziffle
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Hu
authors.forename: Andrew
authors.initials: A
authors.lastname: Burghardt
authors.forename: Steven C
authors.initials: SC
authors.lastname: Spusta
authors.forename: Sharmila
authors.initials: S
authors.lastname: Majumdar
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Mary C
authors.initials: MC
authors.lastname: Nakamura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption; D018920:Coculture Techniques; D004792:Enzyme Precursors / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D051379:Mice; D010006:Osteoblasts / Q000166:cytology*; D010022:Osteopetrosis / Q000235:genetics; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011961:Receptors, Fc / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D000072377:Syk Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011961:Receptors, Fc; D011971:Receptors, Immunologic; C484963:Tyrobp protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse