Selective estrogen receptor modulators, acting as agonists of estrogen receptor α in osteoblasts, reduce the TGF-β-induced synthesis of macrophage colony-stimulating factor via inhibition of JNK signaling pathway.

Selective estrogen receptor modulator (SERM) binds to estrogen receptors (ERs) and acts as both an agonist or an antagonist, depending on the target tissue. Raloxifene and bazedoxifene as SERMs are currently used hormone replacement medicines for postmenopausal osteoporosis. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts promotes osteoclastogenesis. We have previously demonstrated that transforming growth factor (TGF)-β induces the synthesis of M-CSF via SMAD2/3, p38 mitogen-activated protein kinase (MAPK), p44/p42 MAPK and c-Jun N-terminal kinase (JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether SERM affects the M-CSF synthesis by TGF-β in MC3T3-E1 cells. Raloxifene and bazedoxifene significantly suppressed the synthesis of M-CSF. PPT, an ERα agonist, but not ERB041, an ERβ agonist, inhibited the release of M-CSF. MPP, an ERα antagonist, reversed the suppression by raloxifene of the M-CSF release. Raloxifene attenuated the TGF-β-induced phosphorylation of JNK but not SMAD3, p42 MAPK and p38 MAPK. Bazedoxifene and PPT also inhibited the phosphorylation of JNK. Furthermore, MPP, an ERα antagonist, reversed the suppression by both raloxifene and bazedoxifene of the phosphorylation of JNK. Our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-β-induced synthesis of M-CSF through ERα-mediated inhibition of JNK pathway in osteoblasts.