Fig. 1

Main signaling pathways of sex hormones on chondrocytes. Wnt signaling pathway (A): Wnt14 binding inhibits the phosphorylation of β-catenin by GSK3, and the unphosphorylated β-catenin then travels into the chondrocyte nucleus to act as an OA phenotype transcription factor [9]. E2 upregulates the expression of SOST, which codes for an inhibitor of Wnt14 called sclerostin [130]. DHEA decreased the expression of β-catenin, resulting in upregulation of MMP13 and downregulation of TIMP1 and COL2A1 [131]. TGF-β signaling pathway (B): E2 upregulates the expression of ALK5 receptors, promoting ACAN and COL2A1 production and inhibiting COL10A1, MMP13, VEGF, OPN, BGLAP, and ALP expression [9, 135, 136]. Cellular energy and survival related pathways (C): PI3K/AKT signaling pathway is downregulated in human cartilage tissues with OA or in OA-like chondrocytes exposed to IL1, TNFα [153, 154]. E2 could function through the PI3K/AKT/NF-κB pathway by inhibiting chondrocyte apoptosis [229], through the PI3K/AKT/FOXO3 pathway by downregulating MMP3 expression and preventing ECM degradation [156]. Upregulated PI3K/AKT/mTOR in OA cartilage is linked to decreased expression of autophagy-related genes [158]. Overexpression of androgen has been shown to promote chondrogenesis and prevent degradation and apoptosis, potentially through mTOR-related signaling inhibition [88]. In addition, E2 inhibited autophagy upregulation to protect chondrocytes via the SIRT1-mediated AMPK/mTOR pathway [165]. Acid environment and cellular inflammation related pathways (D): E2 can increase the mRNA and protein expression levels of ERRα, which in turn led to an increase in SOX9, GDF5, and CYP19A1. Through the ERRα–AMPK–ULK1 signaling pathway, E2 could support autophagy–lysosome pathway-dependent ASIC1a protein degradation and defend against acidosis-induced cytotoxicity [168]. IL1/6 and TNFα activate NF-κB signaling pathways through receptor binding and ultimately help to upregulate expression of ASIC1a. Activation of ASIC1a could aggravate the effects of IL1/6 and TNFα on ECM metabolism by increasing MMP3/13 and ADAMTS5 mRNA expression in articular chondrocytes [166]. Extracellular acidification activates ASIC1a, which ultimately leads to the autophagy of articular chondrocytes [167]. Low levels of E2 have been observed to inhibit IL1-induced proteoglycan degradation, downregulating cartilage degeneration [83]. DHEA has been shown to play its protective role against cartilage degeneration through regulation of MMP3, TIMP1, IL1, COX2, and iNOS gene expression [33, 169]. MicroRNA related pathways (E): IL1 stimulation increased miR-203 expression [171]. MiR-203 directly targets ERα, followed by downregulation of ACAN and COL2A1 [170]. The estrogen/ER/miR-140 pathway inhibited IL1-induced cartilage matrix degradation [76]. LRP low density lipoprotein receptor-related protein, FZD frizzled receptor, GSK3 glycogen synthase kinase 3, DHEA dehydroepiandrosterone, RUNX2 runt-related transcription factor 2, MMP13 matrix metalloproteinase 13, TIMP1 tissue inhibitor of matrix metalloproteinase 1, COL2A1 type II collagen, E2 estradiol, ER estrogen receptor, TGFβ transforming growth factor beta, ALK5 activin-like kinase 5, SOX9 sry-type high-mobility-group box transcription factor 9, ACAN aggrecan, VEGF vascular endothelial growth factor, OPN osteopontin, OC osteocalcin, ALP alkaline phosphatase, SIRT1 silencing information regulator 2 related enzyme 1, AMPK AMP-activated protein kinase, mTOR mammalian target of rapamycin, ULK unc-51-like kinase, ERRα estrogen‑related receptor α, GDF5 growth and differentiation factor 5, GPER1/GPR30 G-protein coupled estrogen receptor, PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, NF-κB nuclear factor kappa-B, FOXO3 forkhead box O-3, IL1 interleukin 1, ASIC1a acid-sensing ion channel 1a, ADAMTS5 a disintegrin and metalloproteinase with thrombospondin motifs 5, COX2 cyclooxygenase-2, iNOS inducible nitric oxide synthase, TNFα tumor necrosis factor α, MAPK mitogen-activated protein kinases, miR-203 microRNA-203