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

Ismail, H; Miotla-Zarebska, J; Troeberg, L; Tang, X; Stott, B; Yamamoto, K; Nagase, H; Fosang, A; Vincent, A; Saklatvala, J

Journal article

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

Abstract:: Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication status:: In press

Peer review status:: Peer reviewed

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APA Style

Ismail, H., Miotla-Zarebska, J., Troeberg, L., Tang, X., Stott, B., Yamamoto, K., Nagase, H., Fosang, A., Vincent, A., & Saklatvala, J. (2015). JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. Arthritis and Rheumatology (Hoboken, N.J.), n/a-n/a.

MLA Style

Ismail, H., et al. “JNK2 Controls Aggrecan Degradation in Murine Articular Cartilage and the Development of Experimental Osteoarthritis.” Arthritis and Rheumatology (Hoboken, N.J.), Wiley, 2015, pp. n/a-n/a.

Chicago Style

Ismail, H, J Miotla-Zarebska, L Troeberg, X Tang, B Stott, K Yamamoto, H Nagase, A Fosang, A Vincent, and J Saklatvala. 2015. “JNK2 Controls Aggrecan Degradation in Murine Articular Cartilage and the Development of Experimental Osteoarthritis.” Arthritis and Rheumatology (Hoboken, N.J.), n/a-n/a.
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