title: Brief Report: JNK-2 Controls Aggrecan Degradation in Murine Articular Cartilage and the Development of Experimental Osteoarthritis.
abstract: The pathogenesis of osteoarthritis (OA) is poorly understood. Loss of the proteoglycan aggrecan from cartilage is an early event. Recently, we identified a role for the JNK pathway, particularly JNK-2, in human articular chondrocytes in vitro in regulating aggrecan degradation. The present study was undertaken to investigate whether JNK-2 has a similar function in vivo and to examine its role in gene expression.
  
  
  
  Aggrecan fragments were analyzed by Western blotting. OA was induced by destabilization of the medial meniscus (DMM) and assessed at 4, 8, and 12 weeks after surgery. Knee sections were stained with Safranin O. Medial compartments were scored by histologic grading for aggrecan loss and cartilage damage. RNA was extracted from JNK-2(-/-) and wild-type mouse knees 6 hours after DMM or after interleukin-1 stimulation of the proximal epiphysis, and expression of 33 DMM-regulated genes was analyzed with quantitative polymerase chain reaction-customized array cards.
  
  
  
  In vitro, basal and interleukin-1- or tumor necrosis factor-stimulated release of aggrecanase-generated aggrecan fragments was greatly reduced in cartilage from JNK-2(-/-) mice. In the OA model, JNK-2(-/-) mice exhibited significant reduction of aggrecanase-generated fragments and cartilage damage. Of 33 genes investigated, 13 were significantly down-regulated in JNK-2(-/-) mice compared with wild-type mice, following DMM. These included Has1, Adamts4, Tnf, Il6, Il18, Il18rap, Il1a, Inhba, Cd68, Ngf, Ccr2, Wnt16, and Tnfaip6, but not Adamts5.
  
  
  
  Our results demonstrate that JNK-2 regulates aggrecan degradation in cultured murine cartilage and surgically induced OA in vivo following mechanical destabilization of the knee joint. This implicates the JNK signaling pathway in OA and suggests potential novel approaches to therapy.
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Heba M
authors.initials: HM
authors.lastname: Ismail
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Miotla-Zarebska
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Linda
authors.initials: L
authors.lastname: Troeberg
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Tang
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Bryony
authors.initials: B
authors.lastname: Stott
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.affiliation: University of Melbourne Department of Paediatrics, Murdoch Childrens Research Institute, and Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fosang
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Tonia L
authors.initials: TL
authors.lastname: Vincent
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Saklatvala
mesh_terms: D053674:Aggrecans / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics*; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism; D004838:Epiphyses; D005269:Femur; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006621:Hip Joint; D007375:Interleukin-1 / Q000494:pharmacology; D007719:Knee Joint; D008297:Male; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053674:Aggrecans; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048056:Mitogen-Activated Protein Kinase 9; D010450:Endopeptidases; C083641:aggrecanase