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Review
. 2019 Feb 20:132:73-82.
doi: 10.1016/j.freeradbiomed.2018.08.038. Epub 2018 Aug 31.

Reactive oxygen species, aging and articular cartilage homeostasis

Jesalyn A Bolduc  1 , John A Collins  1 , Richard F Loeser  2
Affiliations
Review

Reactive oxygen species, aging and articular cartilage homeostasis

Jesalyn A Bolduc et al. Free Radic Biol Med. .

Abstract

Chondrocytes are responsible for the maintenance of the articular cartilage. A loss of homeostasis in cartilage contributes to the development of osteoarthritis (OA) when the synthetic capacity of chondrocytes is overwhelmed by processes that promote matrix degradation. There is evidence for an age-related imbalance in reactive oxygen species (ROS) production relative to the anti-oxidant capacity of chondrocytes that plays a role in cartilage degradation as well as chondrocyte cell death. The ROS produced by chondrocytes that have received the most attention include superoxide, hydrogen peroxide, the reactive nitrogen species nitric oxide, and the nitric oxide derived product peroxynitrite. Excess levels of these ROS not only cause oxidative-damage but, perhaps more importantly, cause a disruption in cell signaling pathways that are redox-regulated, including Akt and MAP kinase signaling. Age-related mitochondrial dysfunction and reduced activity of the mitochondrial superoxide dismutase (SOD2) are associated with an increase in mitochondrial-derived ROS and are in part responsible for the increase in chondrocyte ROS with age. Peroxiredoxins (Prxs) are a key family of peroxidases responsible for removal of H2O2, as well as for regulating redox-signaling events. Prxs are inactivated by hyperoxidation. An age-related increase in chondrocyte Prx hyperoxidation and an increase in OA cartilage has been noted. The finding in mice that deletion of SOD2 or the anti-oxidant gene transcriptional regulator nuclear factor-erythroid 2- related factor (Nrf2) result in more severe OA, while overexpression or treatment with mitochondrial targeted anti-oxidants reduces OA, further support a role for excessive ROS in the pathogenesis of OA. Therefore, new therapeutic strategies targeting specific anti-oxidant systems including mitochondrial ROS may be of value in reducing the progression of age-related OA.

Keywords: Aging; Cartilage; Cell signaling; Chondrocytes; Osteoarthritis; Reactive oxygen species.

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Conflict of interest statement

The authors declare no-conflicts of interest

Figures

Fig 1.
Fig 1.
Major sources and routes of metabolism for hydrogen peroxide and superoxide relevant to cartilage redox balance. Superoxide (O2) is generated by incomplete reduction of molecular oxygen in the mitochondrial electron transport chain (ETC) and/or through NADPH oxidase enzyme (NOX) and dual oxidase (DUOX) activity. In addition to O2, NOX4 and DUOX1/2 can also generate hydrogen peroxide H2O2. Often, O2 ˙ is dismutated by superoxide dismutase (SOD) to produce H2O2 that is then further reduced to water by either peroxiredoxins (Prxs), catalase (CAT) or glutathione peroxidase (GPx). SOD2 and Prx3 are present in the mitochondria while SOD1 and Prx1,2,4 and 5 are cytosolic Prxs. Once oxidized, Prx dimers are reduced back to Prx monomers by thioredoxin (Trx), thioredoxin reductase (TrxR) and nicotinamide adenine dinucleotide phosphate (NADPH). H2O2 can also react with protein thiols (SH) to form a sulfenic acid (SOH) that can be reduced back to SH (not shown), react with a protein thiol to form a disulfide (not shown) or can react with glutathione (GSH) to form a glutathiolated protein (-SSG) that can be reduced back to the protein thiol by glutathione reductase (Grx).
Fig 2.
Fig 2.. Nitric oxide generation and formation of peroxynitrite.
Nitric oxide synthetases (NOS) utilize oxygen (O2), nicotinamide adenine dinucleotide phosphate (NADPH) and arginine to produce nitric oxide (NO), NADP and citrulline. NO can react with superoxide (O2˙) (produced by sources shown in Figure 1) to form peroxynitrite (ONOO-).
Fig 3.
Fig 3.. Mitochondrial dysfunction, oxidative stress and redox signaling in aging and osteoarthritis.
Age-associated impairment of electron transport chain function resulting in mitochondrial dysfunction coupled with reduced activity of the mitochondrial antioxidant enzymes, SOD2 and Prx3, increases oxidative stress and mitochondrial damage. In the presence of excessive levels of H2O2, Prx3 can be hyperoxidized to form PrxSO2 or PrxSO3 which results in inactivation of Prx activity. In addition, an age and OA related reduction in cytosolic antioxidant capacity alongside an increase in H2O2 production from various sources including NOXs and perhaps lipoxygenases, contributes to elevated levels of H2O2, resulting in cytosolic oxidative stress. Oxidative stress conditions lead to disturbances in homeostatic cell signal transduction, in part by oxidation (including S-sulfenylation) and hyperoxidation of redox sensitive proteins including the cytosolic Prxs 1 and 2. Disruptions in signaling identified in chondrocytes by oxidative stress include activation of pro-catabolic MAP kinase (p38 and ERK) signaling and inhibition of pro-anabolic IGF-1 and BMP7 signaling through inhibition of PI3-kinase, Akt and Smads. This leads to an aging cell phenotype, chondrocyte death and increased cartilage matrix degradation and loss.
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