Targeting TRPC Channels for Control of Arthritis-induced Bone Erosion

Overview

Journal Sci Adv

Date 2025 Jan 15

PMID 39813349

Authors

Suravi Ray

Jamie L McCall

Jin Bin Tian

Jaepyo Jeon

Aidan Douglas

Kendall Tyler

Siyao Liu

Kendyl Berry

Brady Nicewarner

Casey Hall

Klaus Groschner

Bernadett Bacsa

Werner Geldenhuys

Michael X Zhu

Harry C Blair

John B Barnett

Jonathan Soboloff

Affiliations

Soon will be listed here.

Abstract

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