Obesity, Osteoarthritis and Aging: The Biomechanical Links - The Mechanobiology of Obesity and Related Diseases - page 183

studies showing that exercise increases anti-inflammatory mediators. In chondro-
cytes and cartilage explants, cyclic biomechanical loading suppresses NF-jB acti-
vation and down-regulates IL-1a and TNF-a dependent gene transcription [ 94 , 95 ]. A
growing number of studies also indicate that cyclic loading reduces the expression of
inflammatory-induced cartilage catabolic mediators (e.g., matrix metallo-protein-
ases and aggrecanases) and lessens cartilage matrix degradation [ 94 - 101 ]. Thus,
decreased cyclic joint loading may itself increase the susceptibility of joint tissues to
inflammatory stress. An important challenge for the future is to integrate quantitative
measures of systemic and local inflammation with biomechanical exposure data to
better understand how obesity increases the risk of OA through inflammatory
pathways in weight-bearing joints.
4 Redox Signaling and Oxidative Stress in the Obese Joint
4.1 Reactive Oxygen Species, Metabolism, and Mechanical
Loading
A common feature of OA, particularly with aging, is an increase in reactive
oxygen species (ROS) production, cellular oxidation, and cell death [ 102 - 104 ].
ROS are chemically reactive molecules derived from the metabolism of molecular
oxygen [ 105 ]. In chondrocytes, ROS is primarily generated non-enzymatically in
mitochondria and enzymatically by NADPH-oxidase (NOX) [ 106 ]. Nitric oxide, a
reactive nitrogen species often collectively referred to as ROS, is generated
enzymatically by nitric oxide synthase (NOS). ROS encompass a range of mole-
cules with different levels of reactivity. Three of the more prominent types of ROS
in chondrocytes—superoxide anion, hydrogen peroxide, and nitric oxide—are not
as reactive as other types of ROS (e.g., hydroxyl radical and peroxynitrite) but play
important signaling roles in chondrocytes. Hydrogen peroxide is formed by the
rapid dismutation of superoxide anion by superoxide dismutase (SOD). Although
not a free radical, hydrogen peroxide regulates intra-cellular signaling and serves
as a central pro-oxidant secondary messenger by linking hydrogen peroxide
degradation to the reversible oxidation of protein cysteine residues and cellular
redox couples [ 107 , 108 ]. With the development of OA, both non-enzymatic and
enzymatic sources of superoxide anion and hydrogen peroxide production are
elevated in chondrocytes [ 103 , 106 ]. Nitric oxide and peroxynitrite are also ele-
vated in OA chondrocytes [ 109 ], giving further indication that multiple redox-
generating pathways are up-regulated with OA.
Despite the well-established links between ROS production and OA and
between obesity and OA, role of chondrocyte ROS production in obesity-associ-
ated OA is poorly understood. Clinically, end-stage OA cartilage tissue is rarely
differentiated by BMI categories to determine if ROS-producing pathways vary
with obesity status. Given the high prevalence of obesity-associated total knee
arthroplasties, it is likely that many previous observations linking OA to ROS