This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Osteoclasts are inappropriately activated in autoimmune disease states such as rheumatoid arthritis. While signals through RANKL and MCSF are required for osteoclast differentiation, regulation by other receptors is less well defined. We have focused on TREM2, an immune receptor found in osteoclasts. TREM2 associates with DAP12, an ITAM (immunoreceptor tyrosine-based activation motif) containing signaling adapter protein. TREM2/DAP12 signaling is required for osteoclast maturation and activates osteoclast fusion and migration in vitro. Intracellular phosphatases negatively regulate many ITAM adapter proteins in hematopoietic cells. As such, we investigated the role of phosphatases inhibiting TREM2/DAP12 signals in osteoclasts. Our data shows that SH2 domain-containing 5' inositol phosphatase (SHIP1) and DAP12 are associated in osteoclast cell lysates. SHIP1 null preosteoclasts are hyper-responsive to TREM2/DAP12 signaling during osteoclastogenesis indicating that SHIP1 has a functional role in inhibiting this pathway. These data suggest that SHIP1 phosphatase regulates DAP12 signaling in osteoclasts. Using in vitro osteoclastogenesis assays from primary murine osteoclast cultures from C57Bl6 and SHIP1-/- mice we are determining the role of SHIP1 in regulating DAP12 signals. We are mapping the protein-protein interactions between DAP12 and SHIP1. We are determining whether SHIP1 regulates DAP12 activation in response to other stimuli including M-CSF and osteopontin. These studies will reveal the functional nature of SHIP1 regulation of DAP12 signaling as well as the important protein domains required for this regulation in osteoclasts and might lead to novel strategies to inhibit osteoclast differentiation or activation.
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