Celecoxib is the only nonsteroidal anti-inflammatory drug to inhibit bone progression in spondyloarthritis

Abstract

Spondyloarthritis (SpA) is a chronic inflammatory disease thatleads to ankylosis of the axial skeleton. Celecoxib (cyclooxygenase–2 inhibitor, COX-2i) inhibited radiographic progressionin 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-inflammatorydrugs (NSAIDs) inhibited bone progression in SpA,and whether celecoxib had a unique function (independent ofthe COX-inhibitor), compared with the other NSAIDs. We investigatedthe efficacy of various NSAIDs in curdlan-injectedSKG mice (SKGc), an animal model of SpA, analyzed by bonemicro-CT and immunohistochemistry. We also tested the effectof NSAIDs on osteoblast (OB) differentiation and bone mineralizationin primary bone-derived cells (BdCs) from mice, andin ankylosing spondylitis (AS) patients and human osteosarcomacell line (SaOS2). Celecoxib significantly inhibited clinicalarthritis and bone progression in the joints of SKGc, butnot etoricoxib (another COX-2i), nor naproxen (COX-2 nonselective). Both DM–celecoxib, not inhibiting COX-2, andcelecoxib, inhibited OB differentiation and bone mineralizationin the BdCs of mice and AS patients, and in SaOS2, but etoricoxibor naproxen did not. The in silico study indicated thatcelecoxib and 2,5–dimethyl–celecoxib (DM–celecoxib) wouldbind to cadherin–11 (CDH11) with higher affinity than etoricoxiband naproxen. Celecoxib suppressed CDH11-mediated β–cateninsignaling in the joints of SKGc, primary mice cells, and SaOS2cells. Of the NSAIDs, only celecoxib inhibited bone progressionin SKGc and OB differentiation and bone mineralization in theBdCs of mice and AS patients via CDH11/WNT signaling,independent of the COX-2 inhibition.