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Regulation of human osteoclast development by dendritic cell-specific transmembrane protein (DC-STAMP)

2011; Oxford University Press; Volume: 27; Issue: 1 Linguagem: Inglês

10.1002/jbmr.531

1523-4681

Yahui Grace Chiu, Kofi A. Mensah, Edward M. Schwarz, Yawen Ju, Masahiko Takahata, Changyong Feng, Loralee McMahon, David G. Hicks, Ben Panepento, Peter C. Keng, Christopher T. Ritchlin,

Bone Metabolism and Diseases

Abstract Osteoclasts (OC) are bone-resorbing, multinucleated cells that are generated via fusion of OC precursors (OCP). The frequency of OCP is elevated in patients with erosive inflammatory arthritis and metabolic bone diseases. Although many cytokines and cell surface receptors are known to participate in osteoclastogenesis, the molecular mechanisms underlying the regulation of this cellular transformation are poorly understood. Herein, we focused our studies on the text-decoration:underlineendritic text-decoration:underlineell-text-decoration:underlinepecific text-decoration:underlinertext-decoration:underlinenstext-decoration:underlineembrane text-decoration:underlinerotein (DC-STAMP), a seven-pass transmembrane receptor-like protein known to be essential for cell-to-cell fusion during osteoclastogenesis. We identified an text-decoration:underlinemmunoreceptor text-decoration:underlineyrosine-based text-decoration:underlinenhibitory text-decoration:underlineotif (ITIM) in the cytoplasmic tail of DC-STAMP, and developed an anti-DC-STAMP monoclonal antibody 1A2 that detected DC-STAMP expression on human tumor giant cells, blocked OC formation in vitro, and distinguished four patterns of human PBMC with a positive correlation to OC potential. In freshly isolated monocytes, DC-STAMPhigh cells produced a higher number of OC in culture than DC-STAMPlow cells and the surface expression of DC-STAMP gradually declined during osteoclastogenesis. Importantly, we showed that DC-STAMP is phosphorylated on its tyrosine residues and physically interacts with SHP-1 and CD16, an SH2-domain-containing tyrosine phosphatase and an ITAM-associated protein, respectively. Taken together, these data show that DC-STAMP is a potential OCP biomarker in inflammatory arthritis. Moreover, in addition to its effect on cell fusion, DC-STAMP dynamically regulates cell signaling during osteoclastogenesis. © 2012 American Society for Bone and Mineral Research