| Celecoxib, but no other nonsteroidal anti-inflammatory drugs, inhibits bone progression in spondyloarthritis |
Seung Cheol Shim  1,* (Professor), Jin Sun Choi 1,# (Research worker), Ji-Young Kim 1,# (Research worker), Min-joo Ahn 1 (Research worker), Seungtaek Song1 (Research worker), Hanbit Jang 1 (Research worker), Doyoun Kim 2,3 (Research worker), Sung Hoon Choi 4 (Professor), Ye-Soo Park 5 (Professor), Tae-Jong Kim 6 (Professor), Sungsin Jo 7 (Research worker), Tae-Hwan Kim 7,8 (Professor) |
1Division of Rheumatology, Regional Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital,
2Therapeutics & Biotechnology Division, Drug discovery platform research center, Korea Research Institute of Chemical Technology (KRICT),
3Medicinal Chemistry and Pharmacology, Korea University of Science and Technology (UST),
4Department of Orthopaedic Surgery, Hanyang University Hospital,
5Department of Orthopedic Surgery, Guri Hospital, Hanyang University College of Medicine,
6Department of Rheumatology, Chonnam National University Medical School and Hospital,
7Hanyang University Institute for Rheumatology Research (HYIRR),
8Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases |
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Abstract
Spondyloarthritis (SpA) is a chronic inflammatory disease leading to ankylosis of the axial skeleton. Celecoxib (cyclooxygenase-2 inhibitor, COX-2i) inhibited radiographic progression in a clinical study of SpA, but diclofenac (COX-2 non-selective) failed to show the inhibition in the following study. Our study aimed to investigate whether nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited bone progression in SpA, and whether celecoxib had a unique function compared with the other NSAIDs. We investigated the efficacy of various NSAIDs in SKG-curdlan mice (SKGc), an animal model of SpA, analyzed by bone micro-CT and immunohistochemistry. And we tested the effect of NSAIDs on osteoblast (OB) differentiation and bone mineralization in primary bone-derived cells (BdCs) from mice and in ankylosing spondylitis (AS) patients and human osteosarcoma cell line (SaOS2). Celecoxib, not etoricoxib (another COX-2i) nor naproxen (COX-2 non-selective), significantly inhibited clinical arthritis and bone progression in the joints of SKGc. Both DM-celecoxib, not inhibiting COX-2, and celecoxib inhibited OB differentiation and bone mineralization in BdCs of mice and AS patients and in SaOS2, but etoricoxib or naproxen did not. The in-silico study indicated that celecoxib and 2,5-dimethyl-celecoxib (DM-celecoxib) would bind to cadherin-11 (CDH11) with higher affinity than etoricoxib and naproxen. Celecoxib suppressed CDH11-mediated モ-catenin signaling in the joints of SKGc, primary mice cells, and SaOS2 cells. Only celecoxib, but no other NSAIDs, inhibited bone progression in SKGc and OB differentiation and bone mineralization in BdCs of mice and AS patients via CDH11/WNT signaling independent of the COX-2 inhibition.
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| Abstract, Accepted Manuscript [Submitted on April 25, 2024, Accepted on July 11, 2024] |
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