JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis.

The pathogenesis of osteoarthritis (OA) is poorly understood. Loss of the proteoglycan aggrecan from the cartilage is an early event. Recently, we identified a role for the JNK pathway, particularly JNK2, in human articular chondrocytes regulating aggrecan degradation. To understand whether JNK2 plays a similar role in vivo, we investigated the development of OA in JNK2(-/-) mice by using the surgical model of destabilizing the medial meniscus (DMM). The role of JNK2 in gene expression was also investigated.Aggrecan fragments were analysed by western blotting. OA was induced by DMM and analysed at 4, 8, and 12 weeks post-surgery. Knee sections were stained with Safranin O. Medial compartments were scored by histological grading for aggrecan loss and cartilage damage. RNA was extracted from JNK2(-/-) and wild-type knees 6hrs following DMM or after IL1 stimulation of proximal epiphysis. Expression of 33 DMM-regulated genes was analysed by q-PCR customized array cards.Basal and IL-1- or TNF-stimulated release of aggrecanase-generated aggrecan fragments were much reduced in JNK2(-/-) cartilage. In the OA model, JNK2(-/-) mice showed significant reduction of aggrecanase-generated fragments and cartilage damage. Of 33 genes investigated, 13 were significantly down-regulated in JNK2(-/-) mice following DMM compared with wild-type. These included Has1, ADAMTS4, Tnf, IL6, IL18, Inhba, Cd68, Ngf, Ccr2, Wnt16, Tnfaip6 and Il1r, but not ADAMTS-5.JNK2 regulates aggrecan degradation in cultured murine cartilage and surgically-induced OA in vivo following mechanical destabilisation of the knee-joint. This implicates the JNK signalling pathway in OA and suggests novel therapeutic approaches. This article is protected by copyright. All rights reserved.