5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis

Jihee Kim, Gina Ryu, Jeongmin Seo, Miyeon Go, Gyungmin Kim, Sol Yi, Suwon Kim, Hana Lee, June-Yong Lee, Han Sung Kim, Min-Chan Park, Dong Hae Shin, Hyunbo Shim, Wankyu Kim and Soo Young Lee ()
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Jihee Kim: Ewha Womans University
Gina Ryu: Ewha Womans University
Jeongmin Seo: Ewha Womans University
Miyeon Go: Ewha Womans University
Gyungmin Kim: Ewha Womans University
Sol Yi: Ewha Womans University
Suwon Kim: Ewha Womans University
Hana Lee: Yonsei University
June-Yong Lee: Yonsei University College of Medicine
Han Sung Kim: Yonsei University
Min-Chan Park: Yonsei University College of Medicine
Dong Hae Shin: Ewha Womans University
Hyunbo Shim: Ewha Womans University
Wankyu Kim: Ewha Womans University
Soo Young Lee: Ewha Womans University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Osteoarthritis (OA) is a progressive and irreversible degenerative joint disease that is characterized by cartilage destruction, osteophyte formation, subchondral bone remodeling, and synovitis. Despite affecting millions of patients, effective and safe disease-modifying osteoarthritis drugs are lacking. Here we reveal an unexpected role for the small molecule 5-aminosalicylic acid (5-ASA), which is used as an anti-inflammatory drug in ulcerative colitis. We show that 5-ASA competes with extracellular-matrix collagen-II to bind to osteoclast-associated receptor (OSCAR) on chondrocytes. Intra-articular 5-ASA injections ameliorate OA generated by surgery-induced medial-meniscus destabilization in male mice. Significantly, this effect is also observed when 5-ASA was administered well after OA onset. Moreover, mice with DMM-induced OA that are treated with 5-ASA at weeks 8–11 and sacrificed at week 12 have thicker cartilage than untreated mice that were sacrificed at week 8. Mechanistically, 5-ASA reverses OSCAR-mediated transcriptional repression of PPARγ in articular chondrocytes, thereby suppressing COX-2-related inflammation. It also improves chondrogenesis, strongly downregulates ECM catabolism, and promotes ECM anabolism. Our results suggest that 5-ASA could serve as a DMOAD.

Date: 2024
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DOI: 10.1038/s41467-024-45174-6

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