Emerging Players at the Intersection of Chondrocyte Loss of Maturational Arrest, Oxidative Stress, Senescence and Low-Grade Inflammation in Osteoarthritis

Figure 1

Failure of major homeostatic mechanisms contributes to OA pathogenesis. Failure of major homeostatic mechanisms (proteostasis and DNA damage repair networks and mitochondrial respiratory metabolism) in articular chondrocytes is caused by aging or conditions that accelerate tissue aging, such as the obesity-associated systemic low-grade inflammation and/or dietary factors (dyslipidemia and/or hyperglycemia) that impact on mitochondrial function. (a) Homeostasis is tightly controlled by balance between the insulin/IGF_mTOR signaling and SIRT1. In conditions of homeostasis normal mitochondrial function, biogenesis and autophagy (mitophagy) guarantee that the level of ROS is kept to the minimum required for intracellular signaling. Both genomic and mtDNA are preserved from oxidative damage. Proteostasis is guaranteed by the correct functioning of the unfolded protein response and clearance via autophagy or the ubiquitin-proteasome system. (b) Deranged metabolic factors together with aging contribute to mitochondrial dysfunction, accumulation of ROS and RNS that increase the level of protein misfolding and aggregation, and impact on the integrity of both mitochondrial and genomic DNA. Accumulation of DNA damage cannot be efficiently corrected because mitochondrial dysfunction leads to failure of the energy supply required by the DNA damage response. Persistent DNA damage is responsible for chronic NF-κB activation, and inflammation, leading to the “metabolic syndrome.” A positive feedback loop between metabolic syndrome and inflammation is even worsened by excessive ROS and RNS produced by the dysfunctional mitochondria. Persistent DNA damage is also responsible for p53 activation, with functional consequences for the cells that include cell cycle arrest, senescence, or apoptosis according to an increasing degree.

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