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

## TL;DR

Cold exposure worsens osteoarthritis by reducing APOE in cartilage, causing lipid buildup and cell death, but this can be reversed with a specific treatment.

## Contribution

Identifies APOE downregulation as a novel mechanism linking cold exposure to osteoarthritis progression and proposes a therapeutic strategy.

## Key findings

- Cold exposure significantly downregulates Apoe expression in chondrocytes, correlating with OA exacerbation.
- RGX-104 treatment restores APOE and mitigates cold-induced OA progression.
- APOE suppression leads to lipid accumulation, mitochondrial dysfunction, and chondrocyte apoptosis.

## 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.

Cold exposure is shown to aggravate osteoarthritis (OA) by suppressing chondrocyte APOE, triggering lipid accumulation, mitochondrial dysfunction, and apoptosis. Therapeutic APOE activation via RGX-104 mitigates cold-induced OA progression.

APOE downregulation in chondrocytes was identified as the key mechanism linking cold exposure to aggravated OA pathology.Lipid accumulation and elevated ROS production were observed in Apoe-deficient chondrocytes under cold conditions.Mitochondrial dysfunction and chondrocyte apoptosis were induced by cold-mediated APOE suppression.APOE down-regulation in cold promoted lipid content and ROS production in chondrocytes.Therapeutic activation of Apoe using RGX-104 was demonstrated to alleviate cold-induced OA progression.

APOE downregulation in chondrocytes was identified as the key mechanism linking cold exposure to aggravated OA pathology.

Lipid accumulation and elevated ROS production were observed in Apoe-deficient chondrocytes under cold conditions.

Mitochondrial dysfunction and chondrocyte apoptosis were induced by cold-mediated APOE suppression.

APOE down-regulation in cold promoted lipid content and ROS production in chondrocytes.

Therapeutic activation of Apoe using RGX-104 was demonstrated to alleviate cold-induced OA progression.

Cold exposure is shown to aggravate osteoarthritis (OA) by suppressing chondrocyte APOE, triggering lipid accumulation, mitochondrial dysfunction, and apoptosis. Therapeutic APOE activation via RGX-104 mitigates cold-induced OA progression.