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

Abstract

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.

Insights and implications of sexual dimorphism in osteoporosis

“…99 Increasing attention has recently been directed toward the emerging roles of ERα in mechanotransduction signaling pathways in articular chondrocytes. 181 In line with the above notion, bone formation was shown to be enhanced via upregulation of ERα in the process of fracture healing in mice following an application of mechanical strain induced by high-frequency low-magnitude vibration. 182 Specifically, ERα activation induces the differentiation of MSCs into osteoblasts, the differentiation of osteoblasts into osteocytes, and apoptosis of osteoclasts.…”

Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation

“…Dependent on integrins, the cytoskeleton, ion channels and primary cilia, condylar chondrocytes are capable of converting mechanical stimuli into biochemical signals, thereby triggering subsequent biological responses. This process of mechanotransduction signaling involves mechanosensors, mechanotransducers, and mechanoimpactors ( Wang et al, 2023 ). Mechanosensors are the elements that directly sense and transduce the mechanical signals.…”

“…For Under mechanical loading, cells respond to physical stimuli and convert into biochemical signals, which induce a series of cellular responses followed by changes in cell phenotype as well as the structure and composition of the ECM. This process is called mechanotransduction and is dependent on mechanosensitive elements, mainly integrins, the cytoskeleton, ion channels and primary cilia ( Hodgkinson et al, 2022 ; Wang et al, 2023 ). In this section, we focus on reported elements in condylar chondrocytes ( Figure 1 ).…”

“…Integrins, a group of mechanosensitive cell-surface receptors consisting of α and β subunits, mediate extracellular-intracellular signaling transduction and subsequently activate several intracellular cascades, which are essential for the maintenance of homeostasis and regulation of cellular biological functions ( Humphries, 2000 ; Kechagia et al, 2019 ). αVβ1, αVβ3, αVβ5, α1β1, α3β1, α5β1 and α10β1 are the major integrins expressed in chondrocytes ( Wang et al, 2023 ). High expression levels of α5β1 and αVβ3 in the hypertrophic layer of condylar cartilage have been reported ( Yanoshita et al, 2020 ).…”

Mechanotransduction and inflammation: an updated comprehensive representation

“…The mechano core map 9 has been updated with new entities f rom 12 recent (2015-2023) comprehensive review articles [11][12][13][14][15][16][17][18][19][20][21][22] and f ive research articles specif ically related to the review of the role of the aryl hydrocarbon receptor (AhR [23][24][25][26][27] ), which, in addition to its recognized role as a sensor f or endo -and xenobiotics, has recently been recognized as having role in the transduction of mechanical signals, particularly those associated with endothelial f luid shear stress and directional migration. Publications have been manually selected using the keywords "mechanotransduction", "mechanical stimuli", and "mechanical f orce".…”