In vitro study to identify ligand-independent function of estrogen receptor-α in suppressing DNA damage-induced chondrocyte senescence

In osteoarthritis (OA), chondrocytes undergo many pathological alternations that are linked with cellular senescence. However, the exact pathways that lead to the generation of a senescence-like phenotype in OA chondrocytes are not clear. Previously, we found that loss of estrogen receptor-alpha (ER alpha) was associated with an increased senescence level in human chondrocytes. Since DNA damage is a common cause of cellular senescence, we aimed to study the relationship among ER alpha levels, DNA damage, and senescence in chondrocytes. We first examined the levels of ER alpha, representative markers of DNA damage and senescence in normal and OA cartilage harvested from male and female human donors, as well as from male mice. The influence of DNA damage on ER alpha levels was studied by treating human chondrocytes with doxorubicin (DOX), which is an often-used DNA-damaging agent. Next, we tested the potential of overexpressing ER alpha in reducing DNA damage and senescence levels. Lastly, we explored the interaction between ER alpha and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) pathway. Results indicated that the OA chondrocytes contained DNA damage and displayed senescence features, which were accompanied by significantly reduced ER alpha levels. Overexpression of ER alpha reduced the levels of DNA damage and senescence in DOX-treated normal chondrocytes and OA chondrocytes. Moreover, DOX-induced the activation of NF-kappa B pathway, which was partially reversed by overexpressing ER alpha. Taken together, our results demonstrated the critical role of ER alpha in maintaining the health of chondrocytes by inhibiting DNA damage and senescence. This study also suggests that maintaining the ER alpha level may represent a new avenue to prevent and treat OA.

Automated summary

This study found that decreased estrogen receptor alpha (ER alpha) levels are associated with cellular senescence in osteoarthritis (OA) chondrocytes. Overexpressing ER alpha can reduce DNA damage and senescence levels in chondrocytes. These findings suggest that maintaining ER alpha levels may be a new approach to prevent and treat OA.