Choi Jin Sun, Kim Ji-Young, Ahn Min-Joo, Song Seungtaek, Kim Doyoun, Choi Sung Hoon, Park Ye-Soo, Kim Tae-Jong, Jo Sungsin, Kim Tae-Hwan, Shim Seung Cheol
Division of Rheumatology, Regional Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon 35015, Korea.
Therapeutics & Biotechnology Division, Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology (UST), Daejeon 34113, Korea.
BMB Rep. 2025 Mar;58(3):140-145. doi: 10.5483/BMBRep.2024-0062.
Spondyloarthritis (SpA) is a chronic inflammatory disease that leads to ankylosis of the axial skeleton. Celecoxib (cyclooxygenase-2 inhibitor, COX-2i) inhibited radiographic progression in a clinical study of SpA, but in the following study, diclofenac (COX-2 non-selective) failed to show that inhibition. Our study aimed to investigate whether nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited bone progression in SpA, and whether celecoxib had a unique function (independent of the COX-inhibitor), compared with the other NSAIDs. We investigated the efficacy of various NSAIDs in curdlan-injected SKG mice (SKGc), an animal model of SpA, analyzed by bone micro-CT and immunohistochemistry. We also 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 significantly inhibited clinical arthritis and bone progression in the joints of SKGc, but not etoricoxib (another COX-2i), nor naproxen (COX-2 nonselective). Both DM-celecoxib, not inhibiting COX-2, and celecoxib, inhibited OB differentiation and bone mineralization in the 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 β-catenin signaling in the joints of SKGc, primary mice cells, and SaOS2 cells. Of the NSAIDs, only celecoxib inhibited bone progression in SKGc and OB differentiation and bone mineralization in the BdCs of mice and AS patients via CDH11/WNT signaling, independent of the COX-2 inhibition. [BMB Reports 2025; 58(3): 140-145].
脊柱关节炎（SpA）是一种导致中轴骨骼强直的慢性炎症性疾病。塞来昔布（环氧化酶-2抑制剂，COX-2i）在一项SpA临床研究中抑制了影像学进展，但在随后的研究中，双氯芬酸（非选择性COX-2）未能显示出这种抑制作用。我们的研究旨在调查非甾体抗炎药（NSAIDs）是否能抑制SpA中的骨进展，以及与其他NSAIDs相比，塞来昔布是否具有独特功能（独立于COX抑制剂）。我们通过骨显微CT和免疫组织化学分析，研究了各种NSAIDs在注射了凝胶多糖的SKG小鼠（SKGc）（一种SpA动物模型）中的疗效。我们还测试了NSAIDs对小鼠、强直性脊柱炎（AS）患者的原代骨源细胞（BdCs）以及人骨肉瘤细胞系（SaOS2）中破骨细胞（OB）分化和骨矿化的影响。塞来昔布显著抑制了SKGc关节中的临床关节炎和骨进展，但依托考昔（另一种COX-2i）和萘普生（非选择性COX-2）则没有。既不抑制COX-2的DM-塞来昔布和塞来昔布，均抑制了小鼠和AS患者的BdCs以及SaOS2中的OB分化和骨矿化，但依托考昔或萘普生则没有。计算机模拟研究表明，塞来昔布和2,5-二甲基塞来昔布（DM-塞来昔布）与钙黏蛋白-11（CDH11）的结合亲和力高于依托考昔和萘普生。塞来昔布在SKGc、原代小鼠细胞和SaOS2细胞的关节中抑制了CDH11介导的β-连环蛋白信号传导。在NSAIDs中，只有塞来昔布通过CDH11/WNT信号传导抑制了SKGc中的骨进展以及小鼠和AS患者的BdCs中的OB分化和骨矿化，这与COX-2抑制无关。[《BMB报告》2025年；58(3): 140 - 145]
