Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J

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Osteoclasts are responsible for bone resorption not only in physiological bone development and remodeling, but also in diseases characterized by inflammatory osteolysis, such as rheumatoid arthritis (RA). Inflammatory bone resorption is complex and resistant to standard anti-resorptive therapies. Moreover, current treatments of osteolysis often cause long-term side effects, including bone remodeling/repair defects and/or immunosuppression. Therefore, there is an important medical unmet need to discover new mechanisms that predominantly or selectively regulate inflammatory osteoclastogenesis, minimizing undesirable effects on bone remodeling or immune response in disease settings. These mechanisms are much less understood. We have focused particular attention on TNF-mediated osteoclastogenesis and bone destruction since TNF is a key pathogenic factor driving inflammatory bone resorption. In the previous project period, we identified the transcription repressor RBP-J as a crucial negative regulator that prominently restrains TNF-induced osteoclastogenesis and inflammatory bone resorption, but not RANKL-induced osteoclastogenesis and bone remodeling. However, the downstream targets of RBP-J specifically involved in TNF-mediated osteoclastogenesis are not well understood. In this application, we identified Hs2st1 as a direct RBP-J target in TNF-induced osteoclastogenesis. Hs2st1 is a heparan sulfate (HS) biosynthetic enzyme that adds sulfate to the 2-O-position of the HS chain on cellular surface. HS sulfation mediated by Hs2st1 affects the interaction between HS and their binding proteins, thereby modulating various cellular activities. RBP-J deficiency enables TNF to turn on the expression of Hs2st1 in osteoclast differentiation. However, the function of and mechanisms mediated by Hs2st1 in osteoclastogenesis, especially in inflammatory settings, are unclear. We found that both RBP-J and Hs2st1 predominantly regulate TNF-induced, but minimally affect RANKL-induced osteoclastogenesis and basal bone mass. Based on our preliminary results, in this proposal, we will 1) investigate the role of Hs2st1 and RBP- J-Hs2st1 axis in vivo in inflammatory bone resorption using genetic approaches, and 2) investigate the mechanisms by which Hs2st1 promotes TNF-induced osteoclastogenesis. We found that Hs2st1 suppresses TNF-induced endogenous IFNβ pathway, a key autocrine feedback inhibitory loop for osteoclastogenesis. Thus, we will primarily focus on the regulation of IFNβ pathway by Hs2st1 in this aim. Successful completion of the proposed studies will establish a novel paradigm wherein a previously unrecognized network mediated by RBP-J, RBP-J new target Hs2st1, HS and HS specific binding proteins specifically governs inflammatory osteoclastogenesis. Since this network appears not to impact physiological osteoclastogenesis and bone remodeling, the players and mechanisms identified in this paradigm will provide a rational framework for developing attractive therapeutic approaches for suppressing inflammatory bone resorption, minimizing side effect on bone remodeling/repair.