title: Stress-Induced Activation of Apoptosis Signal-Regulating Kinase 1 Promotes Osteoarthritis.
abstract: Apoptosis signal-regulated kinase 1 (ASK1) has been shown to affect a wide range of cellular processes including stress-related responses, cytokine and growth factor signaling, cell cycle and cell death. Recently, we reported that lack of ASK1 slowed chondrocyte hypertrophy, terminal differentiation and apoptosis resulting in an increase in trabecular bone formation. Herein, we investigated the role of ASK1 in the pathogenesis of osteoarthritis (OA). Immunohistochemistry performed on articular cartilage samples from patients with OA showed ASK1 expression increased with OA severity. In vitro analysis of chondrocyte hypertrophy, maturation and ASK1 signaling in embryonic fibroblasts from ASK1 knockout (KO) and wild type (WT) mice was examined. Western analysis demonstrated an increase in ASK1 signaling commensurate with chondrogenic maturation during differentiation or in response to stress by the cytokines, tumor necrosis factor alpha or interleukin 1 beta in WT, but not in ASK1 KO embryonic fibroblasts. Surgically induced moderate or severe OA or OA due to natural aging in WT and ASK1 KO mice was assessed by microCT of subchondral bone, immunohistochemistry, histology, and OARSI scoring. Immunohistochemistry, microCT and OARSI scoring all indicated that the lack of ASK1 protected against OA joint degeneration, both in surgically induced OA and in aging mice. We propose that the ASK1 MAP kinase signaling cascade is an important regulator of chondrocyte terminal differentiation and inhibitors of this pathway could be useful for slowing chondrocyte maturation and cell death observed with OA progression. J. Cell. Physiol. 231: 944-953, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China.
authors.forename: Qian-Shi
authors.initials: QS
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Eaton
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Carol
authors.initials: C
authors.lastname: Diallo
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Freeman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D006984:Hypertrophy; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008592:Menisci, Tibial / Q000187:drug effects / Q000601:surgery; D018345:Mice, Knockout; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology* / Q000473:pathology; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D015415:Biomarkers; D016207:Cytokines; D048848:MAP Kinase Kinase Kinase 5