Negative Regulation of Osteoclastogenesis

破骨细胞生成的负调控

• 批准号: 10372951
• 负责人: Lionel B Ivashkiv
• 金额: $ 41.38万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372951
• 关键词: Biological Assay; Bone Resorption; Bone remodeling; Cell Lineage; Cells; Coupled; Coupling; Development; Disease; Enhancers; Environment; Enzymes; Epigenetic Process; Gene Expression Profile; Generations; Genes; Goals; Histones; Human; Hypoxia; Implant; Infection; Inflammation; Inflammatory; Interferons; Interleukin-1; Knowledge; Link; MAP Kinase Gene; Mediating; Medical; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Musculoskeletal; Myelogenous; Orthopedics; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Pathologic; Pathway interactions; Patients; Periodontitis; Phase; Physiological; Regulation; Resistance; Rheumatoid Arthritis; Signal Induction; Signal Transduction; Site; Synovial Membrane; TNF gene; TNFSF11 gene; Therapeutic; Transcription Factor AP-1; Work; base; bone; bone erosion; bone loss; bone mass; chromatin modification; chromatin remodeling; cofactor; cytokine; epigenome; epigenomics; genetic variant; in vivo Model; inflammatory bone loss; novel strategies; novel therapeutic intervention; osteoclastogenesis; pathologic bone resorption; promoter; therapeutic target; transcription factor

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.

髓系破骨细胞是唯一有效的骨吸收细胞。许多病理状况

项目成果

The relative timing of exposure to phagocytosable particulates and to osteoclastogenic cytokines is critically important in the determination of myeloid cell fate.

• DOI: 10.4049/jimmunol.0902808
• 发表时间: 2010-07-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: James DE;Nestor BJ;Sculco TP;Ivashkiv LB;Ross FP;Goldring SR;Purdue PE
• 通讯作者: Purdue PE

Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-gamma in human osteoclast precursors.

• DOI: 10.4049/jimmunol.0900072
• 发表时间: 2009-12-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Ji JD;Park-Min KH;Shen Z;Fajardo RJ;Goldring SR;McHugh KP;Ivashkiv LB
• 通讯作者: Ivashkiv LB

Role of Lysine-Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia-Inducible Factor 1α and E2F1.

• DOI: 10.1002/art.42074
• 发表时间: 2022-06
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: Doi, Kohei;Murata, Koichi;Ito, Shuji;Suzuki, Akari;Terao, Chikashi;Ishie, Shinichiro;Umemoto, Akio;Murotani, Yoshiki;Nishitani, Kohei;Yoshitomi, Hiroyuki;Fujii, Takayuki;Watanabe, Ryu;Hashimoto, Motomu;Murakami, Kosaku;Tanaka, Masao;Ito, Hiromu;Park-Min, Kyung-Hyun;Ivashkiv, Lionel B.;Morinobu, Akio;Matsuda, Shuichi
• 通讯作者: Matsuda, Shuichi

Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling.

• DOI: 10.1002/art.27200
• 发表时间: 2010-02
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Kalliolias, George D.;Zhao, Baohong;Triantafyllopoulou, Antigoni;Park-Min, Kyung-Hyun;Ivashkiv, Lionel B.
• 通讯作者: Ivashkiv, Lionel B.

IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression.

• DOI: 10.4049/jimmunol.0804165
• 发表时间: 2009-08-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Park-Min KH;Ji JD;Antoniv T;Reid AC;Silver RB;Humphrey MB;Nakamura M;Ivashkiv LB
• 通讯作者: Ivashkiv LB