JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis.
<p><strong>Objectives:</strong> 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 ag...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2015
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| _version_ | 1797105005260439552 |
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| author | Ismail, H Miotla-Zarebska, J Troeberg, L Tang, X Stott, B Yamamoto, K Nagase, H Fosang, A Vincent, A Saklatvala, J |
| author_facet | Ismail, H Miotla-Zarebska, J Troeberg, L Tang, X Stott, B Yamamoto, K Nagase, H Fosang, A Vincent, A Saklatvala, J |
| author_sort | Ismail, H |
| collection | OXFORD |
| description | <p><strong>Objectives:</strong> 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.</p> <p><strong>Methods:</strong> 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.</p> <p><strong>Results:</strong> 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.</p> <p><strong>Conclusions:</strong> 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.</p> |
| first_indexed | 2024-03-07T06:41:21Z |
| format | Journal article |
| id | oxford-uuid:f964db46-a112-450c-b646-c6146d6f956e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:41:21Z |
| publishDate | 2015 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:f964db46-a112-450c-b646-c6146d6f956e2022-03-27T12:57:38ZJNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f964db46-a112-450c-b646-c6146d6f956eEnglishSymplectic Elements at OxfordWiley2015Ismail, HMiotla-Zarebska, JTroeberg, LTang, XStott, BYamamoto, KNagase, HFosang, AVincent, ASaklatvala, J<p><strong>Objectives:</strong> 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.</p> <p><strong>Methods:</strong> 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.</p> <p><strong>Results:</strong> 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.</p> <p><strong>Conclusions:</strong> 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.</p> |
| spellingShingle | Ismail, H Miotla-Zarebska, J Troeberg, L Tang, X Stott, B Yamamoto, K Nagase, H Fosang, A Vincent, A Saklatvala, J JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. |
| title | JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. |
| title_full | JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. |
| title_fullStr | JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. |
| title_full_unstemmed | JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. |
| title_short | JNK2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. |
| title_sort | jnk2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis |
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