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
  • 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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