TRPC公司
骨侵蚀
关节炎
化学
医学
瞬时受体电位通道
内科学
受体
作者
Suravi Ray,Jamie L. McCall,Jinbin Tian,Jaepyo Jeon,Aidan Douglas,Kendall Tyler,Stanley Liu,Kendyl Berry,Brady Nicewarner,Casey Hall,Klaus Groschner,Bernadett Bacsa,Werner J. Geldenhuys,Michael X. Zhu,Harry C. Blair,John B. Barnett,Jonathan Soboloff
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2025-01-15
卷期号:11 (3)
标识
DOI:10.1126/sciadv.abm9843
摘要
Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca 2+ -selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels. While ELP-004 minimally affected physiological RANKL-induced osteoclast maturation in murine bone marrow– and spleen-derived myeloid cells (BMSMCs) and human PBMC-derived cells, it potently interfered with osteoclast maturation driven by TNFα or LTB4. The contribution of TRPC channels to osteoclastogenesis was examined using BMSMCs derived from TRPC4 −/− or TRPC(1–7) −/− mice, again revealing preferential interference with osteoclastogenesis driven by proinflammatory cytokines. ELP-004 also reduced bone erosion in a mouse model of rheumatoid arthritis. These investigations reveal TRPC channels as critical mediators of inflammatory bone erosion and provide insight into the major target of ELP-004, a drug currently in preclinical testing as a therapeutic for inflammatory arthritis.
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