The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase

A. Mócsai, Mary Beth Humphrey, Jessica A G Van Ziffle, Yongmei Hu, Andrew Burghardt, Steven C. Spusta, Sharmila Majumdar, Lewis L. Lanier, Clifford A. Lowell, Mary C. Nakamura

Research output: Contribution to journalArticle

332 Citations (Scopus)

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 γ-chain (FcRγ), are severely osteopetrotic. DAP12-/-FcRγ-/- 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-/- FcRγ-/- 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-κB ligand cytokines, DAP12 and FcRγ 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.

Original languageEnglish
Pages (from-to)6158-6163
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number16
DOIs
Publication statusPublished - Apr 20 2004

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Fc Receptors
Osteoclasts
Protein-Tyrosine Kinases
Immunoreceptor Tyrosine-Based Activation Motif
Proteins
Macrophage Colony-Stimulating Factor Receptors
Syk Kinase
Bone and Bones
Cytokine Receptors
src Homology Domains
Bone Resorption
Coculture Techniques
Osteoblasts
Osteogenesis
Bone Marrow Cells
Osteoporosis
Immune System
Phosphorylation
Ligands

ASJC Scopus subject areas

  • Genetics
  • General

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The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase. / Mócsai, A.; Humphrey, Mary Beth; Van Ziffle, Jessica A G; Hu, Yongmei; Burghardt, Andrew; Spusta, Steven C.; Majumdar, Sharmila; Lanier, Lewis L.; Lowell, Clifford A.; Nakamura, Mary C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 16, 20.04.2004, p. 6158-6163.

Research output: Contribution to journalArticle

Mócsai, A. ; Humphrey, Mary Beth ; Van Ziffle, Jessica A G ; Hu, Yongmei ; Burghardt, Andrew ; Spusta, Steven C. ; Majumdar, Sharmila ; Lanier, Lewis L. ; Lowell, Clifford A. ; Nakamura, Mary C. / The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 16. pp. 6158-6163.
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AU - Humphrey, Mary Beth

AU - Van Ziffle, Jessica A G

AU - Hu, Yongmei

AU - Burghardt, Andrew

AU - Spusta, Steven C.

AU - Majumdar, Sharmila

AU - Lanier, Lewis L.

AU - Lowell, Clifford A.

AU - Nakamura, Mary C.

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