Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Ray, S; McCall, JL; Tian, JB; Jeon, J; Douglas, A; Tyler, K; Liu, S; Berry, K; Nicewarner, B; Hall, C; Groschner, K; Bacsa, B; Geldenhuys, W; Zhu, MX; Blair, HC; Barnett, JB; Soboloff, J.
Targeting TRPC channels for control of arthritis-induced bone erosion.
Sci Adv. 2025; 11(3): eabm9843
Doi: 10.1126/sciadv.abm9843
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- Co-Autor*innen der Med Uni Graz
- Bacsa Bernadett
- Groschner Klaus
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- TRPC Cation Channels - metabolism, antagonists & inhibitors
- Humans - administration & dosage
- Mice - administration & dosage
- Osteoclasts - metabolism, drug effects
- Bone Resorption - metabolism, drug therapy, etiology, pathology
- Osteogenesis - drug effects
- Disease Models, Animal - administration & dosage
- Mice, Knockout - administration & dosage
- Arthritis, Rheumatoid - metabolism, drug therapy, pathology, etiology
- Mice, Inbred C57BL - administration & dosage