Obesity, Osteoarthritis and Aging: The Biomechanical Links - The Mechanobiology of Obesity and Related Diseases - page 181

[ 70 ]. These findings support an association between hand OA and several com-
ponents of the 'metabolic syndrome' and suggest a common underlying cause of
disease. Hand OA is positively associated with total and percent body fat in men
and women [ 71 ]. Furthermore, in men, hand OA is increased with elevated waist-
to-hip ratio and visceral adipose tissue mass [ 71 ]. Several studies have investigated
the association between hand OA and circulating levels of adipokines. In cross-
sectional study designs, leptin, adiponectin, and resistin are not associated with
differences in the radiographic severity of hand OA [ 72 , 73 ]. However, longitu-
dinally, elevated adiponectin levels, but not altered leptin or resistin, reduce the
progression of hand OA [ 74 ]. The negative association between adiponectin and
hand OA suggests an important metabolic link as adiponectin protects against
insulin resistance by improving glucose metabolism. We also recently reported
that systemic adiponectin levels were negatively correlated with OA in the tibial
plateau after statistically controlling for body fat differences in mice fed a very
high fat diet [ 75 ]. However, current evidence for a protective role of adiponectin
on cartilage homeostasis is less conclusive. Several studies suggest a more pro-
inflammatory and pro-catabolic effect of adiponectin on cartilage, although not all
evidence support these findings, perhaps due to differences in the isoforms and
source of adiponectin used among studies [ 76 - 79 ]. The extent to which adipo-
nectin levels affect the progression of knee OA is of future interest because hand
OA clusters with OA in other joints and increases the risk of developing knee OA
[ 80 ]. Differences in the risk of progression of hand versus knee OA based on serum
adipokine levels may help to identify how systemic inflammation increases
obesity-associated OA risk by interacting with mechanical factors.
3.2 Interaction of Biomechanics and Inflammation
Although leptin is not associated with the progression of hand OA, increasing
evidence suggests that leptin promotes cartilage catabolism and knee OA by
interacting with mechanosensitive pro-inflammatory pathways (Fig. 3 ). Leptin is a
16-kd polypeptide hormone encoded by the obese (ob) gene [ 81 ]. Leptin is pri-
marily secreted by adipocytes and functions as an afferent signal in a hypothalamic
negative-feedback loop to regulate feeding behavior, adipose tissue mass, and
body weight. Serum leptin levels predict the development of knee cartilage
defects, bone marrow lesions, osteophytes, and synovial inflammation over a
10 year period [ 82 ]. Moreover, we previously reported that feeding female
C57BL/6 J mice a high-fat diet for 45 weeks increased knee OA severity in
proportion to serum leptin levels even when statistically controlling for the effect
of diet and percent body fat [ 83 ]. In joint tissues, leptin is implicated as a syn-
ergistic pro-inflammatory and pro-catabolic mediator when co-stimulated with
other inflammatory mediators, such as IL-1, TNF-a, and IFN-c [ 84 , 85 ]. Leptin
increases nitric oxide production by up-regulating nitric oxide synthase 2, and it
also increases the expression of MMP1, MMP3, and MMP13 [ 84 - 89 ]. These pro-