We studied the effects of estrogen on human fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) focusing on receptor activator of NF-κB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), the osteoclast formation and function regulators that have a substantial role in bone erosion of RA. Estrogen influences osteoporosis and the onset of RA clinically. The cellular responses of RA-FLS to estrogen are initiated via two high-affinity estrogen receptors (ERs). Culture of RA-FLS in the presence of 10-6 M 17β-estradiol (E2) increased expression of estrogen receptor (ER)-α, but not ER-β. OPG mRNA expression was significantly increased, whereas RANKL mRNA was unaffected. E2 treatment also significantly increased the amount of OPG released in the culture supernatant. The increase of OPG and ER-α was specifically antagonized by the pure estrogen antagonist ICI 182780. Tamoxifen, a selective ER moderator, did not increase OPG. The results indicate that estrogen stimulates secretion of OPG from RA-FLS by acting on ER-α, which likely prevents bone erosion in RA.

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