Genistein and 17β-Estradiol Inhibit Extracellular Matrix Production and Chondroitin Sulfate Synthesis in ATDC5 Cells

Genistein is one of the most estrogenic soy isoflavones. This study investigated the effects of genistein and 17β-estradiol (E2) on early chondrogenesis and extracellular matrix (ECM) production in chondrogenic ATDC5 cells. At low concentrations, E2, but not genistein, enhanced chondrogenic differentiation. Higher concentrations of E2 and genistein suppressed ECM production and expression of genes involved in chondroitin sulfate (CS) proteoglycan synthesis, including aggrecan core protein, CS synthases, 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthases, PAPS transporters, and CS sulfotransferases. Genistein exerted a stronger inhibitory effect than E2 and completely abolished the increase in Tgfb1 gene expression during chondrogenic differentiation. Treatment with estrogen receptor antagonist ICI 182780 did not inhibit E2- or genistein-dependent inhibition of chondrogenesis. Furthermore, E2 and genistein exhibited equivalent partial inhibition of transforming growth factor beta (TGF-β)-induced upregulation of Acan and Col2a1 expression. These results indicate that the inhibitory effects of high concentrations of E2 and genistein are dependent on TGF-β, but not the estrogen receptor pathway.