Oxidative stress, autophagy, epigenetic changes and regulation by miRNAs as potential therapeutic targets in osteoarthritis

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• 作者：Sergio Portal-Nú ; ñ ; ez^a ; Pedro Esbrit^a ; Marí ; a José ; Alcaraz^b ; Raquel Largo^c ; ^{rlargo@fjd.es" class="auth_mail" title="E-mail the corresponding author} ; ^{rlargocarazo@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ADAMTS ; a disintegrin and metalloproteinase with thrombospondin motifs ; AGEs ; advanced glycation end products ; ATG ; autophagy-related gene ; Col2 ; type II collagen ; DNMT ; DNA methyltransferase ; ERK ; extracellular signal-regulated kinase ; HDAC ; histone deacetylase ; IGF-I ; insulin growth factor I ; iNOS ; inducible NO synthase ; IL ; interleukin ; MAPK ; mitogen-activated kinase ; miRNA ; micro RNA ; MMP ; metalloproteinase ; mTORC1 ; mammalian target of rapamycin complex 1 ; NF-κB ; nuclear factor κ B ; NO ; nitr
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：108
• 期：Complete
• 页码：1-10
• 全文大小：399 K

文摘

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.