title: Oxidative stress, autophagy, epigenetic changes and regulation by miRNAs as potential therapeutic targets in osteoarthritis.
abstract: Aging is a natural process characterized by the declining ability of the different organs and tissues to respond to stress, increasing homeostatic imbalance and risk of disease. Osteoarthritis (OA) is a multifactorial disease in which cartilage degradation is a central feature. Aging is the main risk factor for OA. In OA cartilage, a decrease in the number of chondrocytes and in their ability to regenerate the extracellular matrix and adequately respond to stress has been described. OA chondrocytes show a senescence secretory phenotype (SSP) consisting on the overproduction of cytokines (interleukins 1 and 6), growth factors (e.g., epidermal growth factor) and matrix metalloproteinases (MMP) (e.g., MMP-3, MMP-13). Reactive Oxygen Species (ROS) play a major role in the induction of the SSP. In chondrocytes, an increase in ROS production leads to hyper-peroxidation, protein carbonylation and DNA damage which alter chondrocyte function. ROS overproduction also induces changes in metabolic pathways such as PI3K-Akt and ERK. Autophagy is a key mechanism for maintaining cell homeostasis by adjusting cell metabolism to nutrient supply and removing damaged organelles. In cartilage, aging-related loss of autophagy leads to cell death and OA, while stimulation of autophagy exerts protective effects on cartilage deterioration. Aging also interferes with epigenetic mechanisms such as activity of histone acetylases that control the pattern of DNA methylation, and induces up- or down-regulation of microRNAs expression. A deeper knowledge of the mechanisms involved in chondrocyte aging could identify potential targets for the treatment of OA, a prevalent and therapeutic-orphan disease.
authors.affiliation: Laboratory of Bone and Mineral Metabolism, IIS-Fundación Jiménez Díaz UAM, Cooperative Research Thematic Network on Aging and Frailty (RETICEF), Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Portal-Núñez
authors.affiliation: Laboratory of Bone and Mineral Metabolism, IIS-Fundación Jiménez Díaz UAM, Cooperative Research Thematic Network on Aging and Frailty (RETICEF), Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Esbrit
authors.affiliation: Department of Pharmacology and IDM, University of Valencia, Cooperative Research Thematic Network on Aging and Frailty (RETICEF), Valencia, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Alcaraz
authors.affiliation: Joint and Bone Research Unit, IIS-Fundación Jiménez Díaz UAM, Cooperative Research Thematic Network on Aging and Frailty (RETICEF), Madrid, Spain. Electronic address: rlargo@fjd.es.
authors.forename: Raquel
authors.initials: R
authors.lastname: Largo
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy; D016922:Cellular Senescence; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D010003:Osteoarthritis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D017382:Reactive Oxygen Species
keywords: Autophagy; Epigenetic changes; Oxidative stress; Regulation by miRNAs; Targets in cell senescence