Biomedical Engineering Reference
In-Depth Information
Loading Dependent
Loading Independent
Body fat
Body weight
Homeostatic Loading
Pathologic Loading
Anti-inflammatory
Lipids
Pro-
inflammatory Lipids
Leptin
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Pro-inflammatory
Mediators
OA
Fig. 3 Obesity induces loading dependent and loading independent pathways to OA. Excess
body weight is associated with a reduction in cyclic physiologic loading, which attenuates
inflammation, and an increase in pro-inflammatory pathologic loading. Similarly, excess body fat
is associated with a reduction in anti-inflammatory lipids and metabolic homeostasis and an
increase in proinflammatory lipids and metabolic dysfunction. Leptin functions synergistically to
increase proinflammatory mediators, although it is unclear if the actions of leptin are loading
dependent or independent to promote OA
catabolic effects of leptin appear to be dependent on tissue disease status and
altered loading or inflammatory conditions associated with obesity. We previously
showed that stimulation with physiologic doses of leptin were not sufficient to
induce or synergistically increase cartilage nitric oxide production or proteoglycan
release in healthy porcine cartilage explants [ 83 ]. Moreover, when OA chondro-
cytes are obtained from patients spanning a range of BMI values from lean to
obese, MMP13 gene expression was only altered by physiologic concentrations of
leptin in cells from obese patients [ 87 ]. It is not known if leptin receptor expression
is increased in chondrocytes from obese patients independent from OA disease
status [ 90 ]. Nevertheless, these studies suggest that leptin interacts with additional
factors associated with obesity to increase knee OA.
Whereas traumatic biomechanical stimuli induce inflammation, physiologic
types of biomechanical loading have been shown to suppress inflammation. Sys-
temically, increased levels of physical activity and cardiorespiratory fitness are
associated with reductions in inflammation [ 91 ], although whether or not increasing
physical activity independent of weight loss also reduces inflammation is not clear
[ 92 ]. In a recent study on the interaction of exercise and obesity using a very high-fat
diet-induced obese mouse model of OA, we found that short-term exercise prevented
obesity-associated proteoglycan loss despite no change in body weight or adiposity
[ 75 ]. Rather than reducing the absolute levels of systemic inflammatory cytokines,
we found that exercise reduced the clustering of metabolic inflammatory markers in
obese mice. In women with knee OA, acute exercise has been shown increase intra-
articular levels of the anti-inflammatory cytokine IL-10 [ 93 ], consistent with other
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