In vitro study to identify ligand-independent function of estrogen receptor-α in suppressing DNA damage-induced chondrocyte senescence.
Xiurui ZhangShiqi XiangYiqian ZhangSilvia LiuGuanghua LeiSophie HinesNing WangHang LinPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2023)
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-α (ERα) 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 ERα levels, DNA damage, and senescence in chondrocytes. We first examined the levels of ERα, 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 ERα 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 ERα in reducing DNA damage and senescence levels. Lastly, we explored the interaction between ERα and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Results indicated that the OA chondrocytes contained DNA damage and displayed senescence features, which were accompanied by significantly reduced ERα levels. Overexpression of ERα reduced the levels of DNA damage and senescence in DOX-treated normal chondrocytes and OA chondrocytes. Moreover, DOX-induced the activation of NF-κB pathway, which was partially reversed by overexpressing ERα. Taken together, our results demonstrated the critical role of ERα in maintaining the health of chondrocytes by inhibiting DNA damage and senescence. This study also suggests that maintaining the ERα level may represent a new avenue to prevent and treat OA.
Keyphrases
- dna damage
- estrogen receptor
- oxidative stress
- dna repair
- nuclear factor
- endoplasmic reticulum
- endothelial cells
- breast cancer cells
- extracellular matrix
- knee osteoarthritis
- diabetic rats
- high glucose
- public health
- rheumatoid arthritis
- transcription factor
- mental health
- risk assessment
- human health
- climate change
- immune response
- single molecule
- cell proliferation
- molecular dynamics
- cancer therapy
- density functional theory
- cell free
- circulating tumor