Faculty, Staff and Student Publications
Publication Date
1-17-2025
Journal
Science Advances
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.
Keywords
Animals, TRPC Cation Channels, Humans, Mice, Osteoclasts, Arthritis, Rheumatoid, Mice, Knockout, Bone Resorption, Osteogenesis, Disease Models, Animal, Tumor Necrosis Factor-alpha, RANK Ligand, Leukotriene B4, Cell Differentiation
DOI
10.1126/sciadv.abm9843
PMID
39813349
PMCID
PMC11734723
PubMedCentral® Posted Date
1-17-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes