Protective effects of mitochondria‐targeted antioxidants and statins on cholesterolinduced osteoarthritis

Abstract

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.

Cholesterol metabolism in pathogenesis of osteoarthritis disease

“…Both models exhibited OA‐like changes, characterized by cartilage degradation, osteophyte formation, changes to subchondral bone architecture. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high‐cholesterol diet compared with controls . These results together emphasize the importance of cholesterol in the pathogenesis of OA.…”

“…Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high-cholesterol diet compared with controls. 25 These results together emphasize the importance of cholesterol in the pathogenesis of OA. Despite the fact that the above studies have demonstrated important and complex interactions between cholesterol and OA, the mechanisms behind this correlation remain unclear.…”

Osteoarthritis year in review 2017: biology

“…Cholesterol-induced joint disease was a common theme among phenotypes this year. Farnaghi et al reported that diet-induced hypercholesterolemia in rats and ApoE-deficient mice (genetic deletion) develop premature/worse spontaneous (metabolic) knee OA that is not only due to ageing 28 . Hypercholesterolemia also worsened post-traumatic OA induced by DMM in mice or meniscectomy in outbred rats in the same study.…”

Saving the joint : new methods for early diagnosis and treatment

“…Moreover, the metabolic syndrome is associated with hypercholesterolemia. This condition results in mitochondrial dysfunction [48] and could further promote inflammation [49] . In addition obesity results in increased and abnormal loading.…”

“…This can reduce loading, metabolic syndrome and systemic inflammation [51] . Additional treatments that have shown potential are the application of statins and mitochondrial protectants [48] . We will focus on this in more detail later.…”