Cold exposure promotes the progression of osteoarthritis through downregulating APOE in cartilage

Abstract Osteoarthritis (OA) is a degenerative joint disease with limited effective therapies. Cold weathers have been shown to affect joint pain in OA patients. However, the impact of cold climate on OA progression is debated, with the underlying mechanisms not fully understood. This study aims to elucidate the role of Apolipoprotein E ( Apoe ) in chondrocytes in relation to OA progression under cold exposure. Both human chondrocytes RNA sequencing and DMM mice OA model revealed that lower temperatures significantly downregulated Apoe expression, correlating with OA exacerbation. Conditional knockout of Apoe in cartilage aggravated cartilage degeneration, leading to lipid accumulation, increased ROS production, mitochondrial dysfunction, and elevated chondrocyte apoptosis. Treatment with RGX-104, an LXRβ agonist, reversely restored APOE expression, mitigated aberrant lipid accumulation and countered the detrimental effects of cold exposure on OA progression. These results suggest that targeting lipid transfer and metabolism, especially through Apoe modulation, may offer therapeutic strategies for OA patients residing in colder climates, such as those at high altitudes and latitudes, and even winter season.