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Roles of DC-STAMP in Osteoclast and Osteoblast (OC::OB) Coupling

Christopher Ritchlin, MD, MPHChristopher Ritchlin, MD, MPH

Principal Investigator

Bone homeostasis is achieved through a dynamic coordination between bone-degrading osteoclast (OC) and bone-synthesizing osteoblast (OB). Excessive OC activity causes “osteoporosis” with weaker and brittle bones, whereas excessive OB activity generates abnormal dense bones with “osteopetrosis” phenotype. An imbalance between OC & OB activities results in skeletal and joint diseases including osteoporosis, arthritis, and non-union bone repair. These diseases impact the quality of life of patients and there are currently no effective medications. To this end, we have focused our research on the role of Dendritic-Cell-Specific-Transmembrane Protein (DC-STAMP), a master regulator during osteoclastogenesis, in OB::OC coupling. Knocking down of DC-STAMP impairs both OB and OC differentiation. Thus, DC-STAMP knockout (KO) mice provide us a unique experimental paradigm for studying OB::OC coupling. We have previously showed that OB are attracted to DC-STAMP+ OC proximity at bone fracture sites in wild-type mice, a phenomena which was not detected in DC-STAMP KO mice. This piece of data, together with the delayed fracture repair phenotype of DC-STAMP KO mice, suggested that DC-STAMP is involved in OB::OC coupling during bone repair. To address the questions (1) whether OB and OC communicate with each other through clastokine-like cytokines (Charles & Aliprantis, Trends Mol. Med. 2014)and (2) whether cell-cell contact is necessary for OB::OC coupling, we are currently establishing different combinations of co-culture between OB and OC resources, developing biological reagents which can trace OB and OC specifically in vivo by IVIS, studying the effects of bone microenvironments on fracture repair by bone marrow reconstitution, and examining the alternations of local cytokine profiles by nanoparticle-based, DC-STAMP-specific medicine delivery on bone fracture sites. Our long-term goal is to delineate the involvement of DC-STAMP in OB::OC coupling at the molecular level and develop biologics which can facilitate bone healing through modulating DC-STAMP activity.

Bone fractures induce the aggregation of DC-STAMP+ osteoclasts to osteoblast proximity.