2. Academic Validation
  3. Targeting TRPC channels for control of arthritis-induced bone erosion

Targeting TRPC channels for control of arthritis-induced bone erosion

  • Sci Adv. 2025 Jan 17;11(3):eabm9843. doi: 10.1126/sciadv.abm9843.
Suravi Ray 1,  Jamie L McCall 2 3,  Jin Bin Tian 4,  Jaepyo Jeon 4,  Aidan Douglas 1,  Kendall Tyler 1,  Siyao Liu 5 6,  Kendyl Berry 2 3,  Brady Nicewarner 3,  Casey Hall 3,  Klaus Groschner 7,  Bernadett Bacsa 7,  Werner Geldenhuys 8 9 10,  Michael X Zhu 4,  Harry C Blair 11,  John B Barnett 2 3 10,  Jonathan Soboloff 1
Affiliations

Affiliations

  • 1 Fels Cancer Institute for Personalized Medicine, Department of Cancer & Cellular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • 2 Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
  • 3 ExesaLibero Pharma, Morgantown, WV 26505, USA.
  • 4 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston TX 77030, USA.
  • 5 Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA.
  • 6 Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX 77030, USA.
  • 7 Medical University of Graz, Division of Medical Physics and Biophysics, Neue Stiftingtalstrasse 6/H03, 8010 Graz, Austria.
  • 8 Department of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26506, USA.
  • 9 Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
  • 10 West Virginia University Cancer Institute, Morgantown, WV 26506, USA.
  • 11 Research Service, VA Medical Centre, Departments of Pathology and of Cell Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
PMID: 39813349 DOI: 10.1126/sciadv.abm9843
Abstract

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the CA2+-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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