Obesity, Osteoarthritis and Aging: The Biomechanical Links - The Mechanobiology of Obesity and Related Diseases - page 186

molecular damage'' [ 122 ]. Oxidative stress may include both reversible and irre-
versible oxidative modifications of proteins, lipids, and DNA, which impair
function and/or promote degradation [ 108 ]. Consequently, cells have evolved a
multifaceted and redundant antioxidant system to maintain physiologic redox
signaling and promote oxidative homeostasis (Fig. 4 ).
Oxidative stress is considered a central feature of OA pathophysiology due to
its effects on inhibiting protein synthesis, activating matrix catabolic pathways,
and increasing cell death [ 106 ]. OA cartilage appears to be at risk of oxidative
stress due to both an increased generation of ROS, as described previously, and a
reduction in antioxidant capacity. Chondrocytes maintain redox homeostasis
through the coordinated actions of extracellular, cytosolic, and mitochondrial
antioxidants. Mammalian SOD exists in three compartment-specific isoforms:
extracellular Cu/Zn SOD (SOD3), cytosolic Cu/Zn SOD (SOD1), and mitochon-
drial Mn SOD (SOD2). These enzymes transform superoxide anion to H 2 O 2 ,
which is further degraded to water and oxygen by glutathione peroxidases, per-
oxiredoxins, and catalase (Fig. 4 ). In addition, thioredoxin and glutathione provide
general antioxidant properties against thiol oxidation, and reduced forms are
required for peroxiredoxin and glutathione peroxidase activity, respectively. Aging
appears to increase the susceptibility of cartilage to oxidative stress independent of
OA status by impairing the glutathione antioxidant capacity, as indicated by an
age-dependent increase in the ratio of oxidized:reduced glutathione in non-dis-
eased cartilage [ 123 ]. In addition, the expression of a number of antioxidant
enzymes are also decreased in cartilage with age and/or OA, including SOD1,
SOD2, SOD3, and glutathione peroxidase 3 [ 124 - 128 ]. Inhibition of SOD2
function in particular has been shown to increase lipid peroxidation and mito-
chondrial damage in chondrocytes [ 119 ].
Surprisingly little is known about the effect of mechanical loading on cartilage
antioxidant function. Exercise increases isoprostane and nitrotyrosine levels in the
cartilage of mice heterozygous for SOD2 [ 129 ]. In addition, a number of studies
have shown that antioxidant supplements targeting superoxide anion and hydrogen
peroxide prevent or reduce the degree of apoptotic chondrocyte death resulting
from injurious mechanical loads [ 118 , 130 ]. One study has reported a positive effect
of cyclic tensile stretching on chondrocyte SOD activity [ 131 ]. Physiologic cyclic
biomechanical loading may enhance antioxidant activities and improve cellular
redox control by preconditioning cartilage with a regulated production of ROS
(Fig. 5 ). Similar preconditioning occurs in skeletal muscle during exercise and with
ischemia in cardiac muscle [ 132 , 133 ]. Low to moderate levels of ROS act as
signaling mediators in pathways involving transcriptional regulation [ 134 , 135 ].
In chondrocytes, NF-jB is an important mechanosensitive transcriptional reg-
ulator of both pro-inflammatory mediators (e.g., NOS2) and cellular antioxidants
(e.g., SOD2) [ 98 , 109 , 136 ]. Activation of the NF-jB signaling pathway is reg-
ulated by several redox-sensitive signaling elements. Physiologic cyclic loads have
been shown to suppress cytokine-induced NF-jB signaling [ 95 ], suggesting that
physiologic loading may improve redox regulation. The regulated production of
ROS

via physiologic biomechanical stimulation may increase endogenous