Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α

In the synovial joint, mechanical force creates an important signal that influences chondrocyte behavior. The conversion of mechanical signals into biochemical cues relies on different elements in mechanotransduction pathways and culminates in changes in chondrocyte phenotype and extracellular matrix composition/structure. Recently, several mechanosensors, the first responders to mechanical force, have been discovered. However, we still have limited knowledge about the downstream molecules that enact alterations in the gene expression profile during mechanotransduction signaling. Recently, estrogen receptor α (ERα) has been shown to modulate the chondrocyte response to mechanical loading through a ligand-independent mechanism, in line with previous research showing that ERα exerts important mechanotransduction effects on other cell types, such as osteoblasts. In consideration of these recent discoveries, the goal of this review is to position ERα into the mechanotransduction pathways known to date. Specifically, we first summarize our most recent understanding of the mechanotransduction pathways in chondrocytes on the basis of three categories of actors, namely mechanosensors, mechanotransducers, and mechanoimpactors. Then, the specific roles played by ERα in mediating the chondrocyte response to mechanical loading are discussed, and the potential interactions of ERα with other molecules in mechanotransduction pathways are explored. Finally, we propose several future research directions that may advance our understanding of the roles played by ERα in mediating biomechanical cues under physiological and pathological conditions.