Biomedical Engineering Reference
In-Depth Information
ATP production and super-physiologic loading induces cell death in a mitochon-
drial-ROS dependent manner. The mechanism(s) by which loading induces these
variable responses are not known, although may include the production of nitric
oxide. Mechanical loading up-regulates the expression of NOS2 and the production
of nitric oxide [
114
]. Nitric oxide is known to impair the activity of complex IV of
the electron transport chain and has also been associated with an increase in cell
death [
115
,
116
]. Impaired electron transport within the electron transport chain
increases electron escape and consequently mitochondrial ROS production.
Enhanced production of mitochondrial ROS and nitric oxide are necessary for
inducing chondrocyte death in the absence of loading [
116
] and thus may also be
critical factors in loading-induced cell death, which also involves the activation of
additional inflammatory pathways and pro-apoptotic factors [
117
,
118
]. The extent
to which pathways activated by traumatic loading are involved in sub-traumatic
joint loading conditions associated with obesity requires further study.
Enhanced metabolic demand or increased reliance on mitochondrial metabo-
lism with obesity may also contribute to increased generation of mitochondrial
ROS, especially under conditions of increased inflammatory stress. In a series of
studies, Blanco and colleagues showed that the activity of electron transport chain
complexes I, II, and III are reduced in OA chondrocytes compared to healthy
controls [
103
]. In addition, citrate synthase activity, a Krebs Cycle enzyme used as
an indirect measure of mitochondrial mass, is increased in OA chondrocytes
compared to controls. This increase in citrate synthase activity may serve a
compensatory role to increase the production of reducing equivalents (e.g., NADH
and FADH
2
) and maintain mitochondrial energy production despite impaired
electron transport [
103
]. Indeed, mitochondrial ATP production is maintained if
not slightly increased in OA chondrocytes [
119
]. Moreover, the pro-inflammatory
cytokines TNF-a and IL-1b, which are increased with obesity, have also been
shown to impair electron transport in healthy chondrocytes [
120
]. Thus, enhanced
inflammation associated with obesity may contribute to OA pathogenesis by
increasing mitochondrial ROS generation. Under acute conditions, inflammation-
induced mitochondrial ROS may facilitate increased rates of glycolysis [
121
].
However, chronic inflammation-induced ROS production without a compensatory
increase in mitochondrial antioxidants may disrupt mitochondrial redox signaling,
resulting in a pathologic state of oxidative stress.
4.2 Antioxidants and Oxidative Stress
The transition from physiologic to pathologic ROS generation is dependent on the
capacity of the antioxidant system to maintain oxidative homeostasis. Conditions
that produce ROS in excess of this capacity may promote a state of oxidative
stress. Given the fundamental role of oxidation-reduction (i.e., ''redox'') reactions
in regulating cell signaling pathways and enzymatic function, an updated defini-
tion of oxidative stress includes a ''disruption of redox signaling and control and/or
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