Myeloid lineage osteoclasts are the sole effective bone-resorbing cells. Osteoclasts are required for the resorptive phase of physiological bone remodeling that maintains musculoskeletal integrity and regulates bone mass. Under physiological conditions the generation and function of osteoclasts is tightly regulated and coupled to the function of bone-forming osteoblast lineage cells. Many pathological conditions associated with excessive bone resorption and bone loss are characterized by loss of normal regulation/coupling, and excessive osteoclastogenesis. The long term goals of this project are to elucidate new 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, periodontitis, infections, and orthopedic implant loosening. Recent work, including contributions from our laboratory, has made clear that potent inflammatory factors, such as the inflammatory cytokines IFN-? and GM-CSF and ligands for Toll-like receptors (TLRs) that sense microbial products and tissue damage, also induce feedback inhibition mechanisms that restrain osteoclastogenesis and thus limit the amount of bone resorption that occurs in inflammatory settings. Little is known about feedback inhibitory mechanisms induced by inflammatory factors to limit osteoclastogenesis. Based on our overarching hypothesis that augmenting feedback mechanisms represents an attractive alternative therapeutic approach to suppress pathologic bone resorption, we have investigated mechanisms by which inflammatory signaling restrains osteoclastogenesis. We have discovered two novel and complementary mechanisms by which inflammatory factors, including ligands for Toll like receptors and ITAM-associated receptors, suppress differentiation of osteoclast precursors. These are: 1. Modulation of a proteolytic pathway that generates a biologically active intracellular fragment of the Fms receptor for M-CSF. 2. Induction of the BCL6 transcriptional repressor to inhibit expression of the 'master regulator'of osteoclastogenesis NFATc1. These novel inhibitory mechanisms target two major nonredundant proteins required for osteoclast differentiation, Fms and NFATc1, and effectively inhibit osteoclastogenesis. We will characterize these inhibitory mechanisms to obtain knowledge that can be used to develop new approaches to suppress osteoclastogenesis and pathologic bone resorption by augmenting these 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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|Ivashkiv, Lionel B; Park, Sung Ho (2016) Epigenetic Regulation of Myeloid Cells. Microbiol Spectr 4:|
|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|
|Ivashkiv, Lionel B (2015) Metabolic-epigenetic coupling in osteoclast differentiation. Nat Med 21:212-3|
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