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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.

SUBMITTER: Zhang QS

PROVIDER: S-EPMC5952048 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Stress-Induced Activation of Apoptosis Signal-Regulating Kinase 1 Promotes Osteoarthritis.

Zhang Qian-Shi QS Eaton Gregory J GJ Diallo Carol C Freeman Theresa A TA

Journal of cellular physiology 20150929 4

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 c ...[more]

PMID: 26405834

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Project description:Tumor necrosis factor-? (TNF?) is a proinflammatory cytokine that is closely linked to the development of cardiovascular disease. TNF? activates NADPH oxidase 1 (Nox1) and reactive oxygen species (ROS), including superoxide (O2·-), production extracellularly is required for subsequent signaling in vascular smooth muscle cells (VSMCs). Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that is activated by oxidation of associated thioredoxin. The role of ASK1 in Nox1-mediated signaling by TNF? is poorly defined. We hypothesized that ASK1 is required for TNF? receptor endocytosis and subsequent inflammatory TNF? signaling. We employed a knockdown strategy to explore the role of ASK1 in TNF? signaling in VSMCs. siRNA targeting ASK1 had no effect on TNF?-induced extracellular O2·- production. However, siASK1 inhibited receptor endocytosis as well as phosphorylation of two endocytosis-related proteins, dynamin1 and caveolin1. Intracellular O2·- production was subsequently reduced, as were other inflammatory signaling steps including NF-?B activation, IL-6 production, inducible nitric oxide synthase and VCAM expression, and VSMC proliferation. Prolonged exposure to TNF? (24 h) increased tumor necrosis factor receptor (TNFR) subtype 1 and 2 expression, and these effects were also attenuated by siASK1. ASK1 coimmunoprecipitated with both Nox1 and the leucine rich repeat containing 8A anion channel, two essential components of the TNFR1 signaling complex. Activation of ASK1 by autophosphorylation at Thr845 occurs following thioredoxin dissociation, and this requires the presence of Nox1. Thus, Nox1 is part of the multiprotein ASK1 signaling complex. In response to TNF?, ASK1 is activated by Nox1-derived oxidants, and this plays a critical role in translating these ROS into a physiologic response in VSMCs. NEW & NOTEWORTHY Apoptosis signal-regulating kinase 1 (ASK1) drives dynamin1 and caveolin1 phosphorylation and TNF? receptor endocytosis. ASK1 modulates TNF?-induced NF-?B activation, survival, and proliferation. ASK1 and NADPH oxidase 1 (Nox1) physically associate in a multiprotein signaling complex. Nox1 is required for TNF?-induced ASK1 activation.

Dataset Information

Stress-Induced Activation of Apoptosis Signal-Regulating Kinase 1 Promotes Osteoarthritis.

Publications

Stress-Induced Activation of Apoptosis Signal-Regulating Kinase 1 Promotes Osteoarthritis.

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