Myeloid lineage osteoclasts are the sole effective bone-resorbing cells. Many pathological conditions associated with excessive bone resorption and bone loss are characterized by excessive osteoclastogenesis. The long term goals of this project are to elucidate new molecular pathways and mechanisms that suppress osteoclastogenesis, with the associated goal of using this information to develop new therapeutic approaches to suppress pathological bone resorption. Inflammation is an important driver of pathological bone loss. Inflammation decreases bone mass by suppressing osteoblast-mediated bone formation, and concomitantly strongly promoting bone resorption by increasing the differentiation and bone-resorbing function of osteoclasts. Thus, inflammation induces local bone erosion/osteolysis at inflammatory sites in diseases such as rheumatoid arthritis (RA), periodontitis, infections, and orthopedic peri-implant loosening. Inflammatory sites are also characterized by hypoxia, which potentiates RANKL-induced osteoclastogenesis by mostly unknown mechanisms. Pathological bone loss in an inflammatory/hypoxic environment such as RA synovium is resistant to standard anti-resorptive therapies, and development of new treatments represents an important unmet medical need. Based on our overarching hypothesis that augmenting inhibitory mechanisms represents an attractive alternative therapeutic approach to suppress pathologic bone resorption, in the previous project period we investigated mechanisms that suppress metabolic and epigenetic pathways important for osteoclastogenesis and are relevant for inflammatory bone loss. We found that IFN-?, well established to restrain bone loss at inflammatory sites, remodeled the epigenome of human osteoclast precursors, resulting in remodeling of chromatin and histone marks at enhancers and promoters of key osteoclast genes. We discovered a new cell-intrinsic negative regulator of osteoclasts, COMMD1, which works by suppressing NF-?B signaling and the induction of anabolic metabolic pathways important for osteoclastogenesis. Allelic variants that increase COMMD1 expression are associated with decreased bone loss in RA patients, and myeloid deletion of Commd1 resulted in increased bone loss in inflammatory models. COMMD1 is inactivated by hypoxia, suggesting that abrogation of this inhibitory mechanism at hypoxic sites such as RA synovium contributes to pathological bone loss. The extrinsic and intrinsic negative regulators, IFN-? and COMMD1 respectively, converged to suppress the expression and function of transcription factors important for induction of osteoclast metabolic genes and pathways. These results identify new inhibitory mechanisms, which we will characterize to obtain knowledge that can be used to develop new approaches to suppress osteoclastogenesis and pathologic bone resorption by augmenting these inhibitory mechanisms therapeutically.
Inflammation activates cells called osteoclasts to damage bones in diseases such as rheumatoid arthritis, periodontitis, infections, and orthopedic implant loosening. We have identified and will investigate new molecular mechanisms that inhibit osteoclasts. This work will generate knowledge that can be used to develop new treatments to limit the amount of pathological bone damage that occurs in various musculoskeletal and inflammatory diseases.
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|Murata, Koichi; Fang, Celestia; Terao, Chikashi et al. (2017) Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis. Immunity 47:66-79.e5|
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|Miller, Christine H; Smith, Sinead M; Elguindy, Mahmoud et al. (2016) RBP-J-Regulated miR-182 Promotes TNF-?-Induced Osteoclastogenesis. J Immunol 196:4977-86|
|Kalliolias, George D; Ivashkiv, Lionel B (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12:49-62|
|Chan, Chun Hin; Fang, Celestia; Yarilina, Anna et al. (2015) BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signaling in a gene-specific manner in human monocytes. Eur J Immunol 45:287-297|
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