The contribution of metabolic factors on the severity of
osteoarthritis (OA) is not fully appreciated. This study aimed to define the effects of
hypercholesterolemia on the progression of OA.
Apolipoprotein E-deficient (
ApoE-/-) mice and rats with diet-induced
hypercholesterolemia (DIHC) rats were used to explore the effects of
hypercholesterolemia on the progression of OA. Both models exhibited OA-like changes, characterized primarily by a loss of
proteoglycans,
collagen and
aggrecan degradation,
osteophyte formation, changes to subchondral bone architecture, and cartilage degradation. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high-
cholesterol diet compared with controls. Clinically relevant doses of free
cholesterol resulted in
mitochondrial dysfunction, overproduction of
reactive oxygen species (ROS), and increased expression of degenerative and hypertrophic markers in chondrocytes and breakdown of the cartilage matrix. We showed that the severity of diet-induced OA changes could be attenuated by treatment with both
atorvastatin and a mitochondrial targeting
antioxidant. The protective effects of the mitochondrial targeting
antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that
hypercholesterolemia precipitates OA progression by
mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the
mitochondrial dysfunction using
antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.-Farnaghi, S., Prasadam, I., Cai, G., Friis, T., Du, Z., Crawford, R.,
Mao, X., Xiao, Y. Protective effects of mitochondria-targeted
antioxidants and
statins on
cholesterol-induced
osteoarthritis.