Regulation of osteoarthritis pathogenesis by cholesterol metabolism

Abstract

Osteoarthritis (OA) is the most common age-related degenerative disease with a large socioeconomic cost, lacking an effective disease-modifying therapy. Among the OA risk factors (i.e. aging, mechanical stress, genetic factors), aging has been considered the most important cause of OA induction. Previous studies revealed that hypertension and arthritis are the most frequently occurring aging-related diseases and the number of patients with hypertension has been known to increase in patients with severe OA symptoms. However since cartilage is avascular tissue, hypertension does not seem to be able to directly affect cartilage. Therefore, I hypothesized that cholesterol, which causes atherosclerosis, affects not only hypertension but also osteoarthritis. Here, I suggested a novel mechanism that cholesterol could regulate the progression of OA by a nuclear receptor, retinoid-related orphan receptor alpha, (RORa) was known as a receptor for cholesterol. I demonstrated that cellular cholesterol levels upregulated in OA chondrocytes and cartilage through uptake of cholesterol-containing oxidized low-density lipoprotein (oxLDL). Cholesterol treatment to chondrocytes and high cholesterol diet (HCD) to OA animal model were shown to promote the OA progression. Among the nuclear receptor ROR family, the expression of RORa was upregulated in OA chondrocytes and cartilage. The transcriptional activity of RORa was regulated by OA-associated signals and cholesterol which is caused by the direct binding of cholesterol to RORa. By direct regulation of the expression of matrix-degrading enzymes in chondrocytes, RORa could regulate the progression of OA in mice. Especially, mutation of RORa inhibited the DMM-induced OA progression in mice fed HCD. These results provide clear evidence that OA is associated with metabolic disease and suggest that the cholesterol-RORa axis could be a novel therapeutic target for treating OA and other cholesterol-related diseases such as atherosclerosis.