Estrogen receptor-α loss accelerates cartilage degradation through CLEC3B-mediated chondrocyte hypertrophy and...

Previous studies in our lab demonstrated that estrogen receptor-α (ERα) levels in cartilage decreased with osteoarthritis (OA). We also defined the essential role of ERα in maintaining the health of chondrocytes. However, most of the studies were conducted in vitro, and the physiological link between ERα loss and cartilage degradation has not been demonstrated using animal models.

In this study, we created OA through the destabilization of the medial meniscus (DMM) in animals with global or cartilage-specific deletion of ERα. We also assessed the impact of ERα loss on chondrocytes' potential in generating hyaline cartilage. Lastly, RNA sequencing was conducted to examine the downstream molecules regulated by ERα.

ERα loss resulted in accelerated OA progression in mice. In addition, removing sexual hormones through ovariectomies in female mice lacking ERα increased the severity of OA. Mechanistically, we found that decreased ERα levels significantly reduced the chondrogenic potential of human chondrocytes and elevated hypertrophy levels upon treatment by transforming growth factor beta (TGF-β). Interestingly, the analysis from RNA sequencing revealed that C-Type Lectin Domain Family 3 Member B (CLEC3B) was significantly upregulated after ERα knockdown in chondrocytes. The finding was further confirmed by western blotting. Importantly, the addition of CLEC3B promoted chondrocytic hypertrophy and elevated inflammation in chondrocytes, partially recapitulating the effect of ERα suppression.

Taken together, the results demonstrated the critical roles of ERα in maintaining the phenotype and functions of chondrocytes and defined that CLEC3B can be a potential therapeutic target for OA treatment.