Deletion ofJNKEnhances Senescence in Joint Tissues and Increases the Severity of Age-Related Osteoarthritis in Mice

Objective To determine the role ofJNKsignaling in the development of osteoarthritis (OA) induced by joint injury or aging in mice. Methods In the joint injury model, 12-week-old wild-type control,JNK1(-/-),JNK2(-/-), andJNK1(fl/fl)JNK2(-/-)aggecan-Cre(ERT)(2)double-knockout mice were subjected to destabilization of the medial meniscus (DMM) (n = 15 mice per group) or sham surgery (n = 9-10 mice per group), andOAwas evaluated 8 weeks later. In the aging experiment, wild-type control,JNK1(-/-), andJNK2(-/-)mice (n = 15 per group) were evaluated at 18 months of age. Mouse knee joints were evaluated by scoring articular cartilage structure, toluidine blue staining, osteophytes, and synovial hyperplasia, by histomorphometric analysis, and by immunostaining for the senescence marker p16(INK)(4a). Production of matrix metalloproteinase 13 (MMP-13) in cartilage explants in response to fibronectin fragments was measured by enzyme-linked immunosorbent assay. Results There were no differences afterDMMsurgery between the wild-type and theJNK-knockout mouse groups in articular cartilage structure, toluidine blue, or osteophyte scores or inMMP-13 production in explants. All 3 knockout mouse groups had increased subchondral bone thickness and area of cartilage necrosis compared to wild-type mice. AgedJNK-knockout mice had significantly worse articular cartilage structure scores compared to the aged wild-type control mice (mean +/- SD52 +/- 24 inJNK1(-/-)mice and 60 +/- 25 inJNK2(-/-)mice versus 32 +/- 18 in controls;P= 0.02 andP= 0.004, respectively).JNK1(-/-)mice also had higher osteophyte scores. Deletion ofJNKresulted in increased expression of p16(INK)(4a)in the synovium and cartilage in older mice. Conclusion JNK1 andJNK2 are not required for the development ofOAin the mouseDMMmodel. Deletion ofJNK1orJNK2is associated with more severe age-relatedOAand increased cell senescence, suggesting thatJNKmay act as a negative regulator of senescence in the joint.