Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation.

摘要: Both estrogens and bisphosphonates attenuate osteocyte apoptosis by activating the extracellular signal-regulated kinases (ERKs). However, whereas activate ERKs via an extranuclear function of estrogen receptor, do so opening connexin 43 hemichannels. Here, we demonstrated that signaling events downstream induced these two stimuli are also distinct. Inhibition requires nuclear accumulation activation transcription factors. On other hand, anti-apoptosis neither nor ERK-dependent Instead, effect is abolished when restricted to nucleus blocking CRM1/exportin1-mediated protein export or expressing nuclear-anchored ERKs, but it unaffected in cells cytoplasmic-anchored ERKs. Connexin 43/ERK-mediated kinase activity cytoplasmic target p90RSK, which turn phosphorylates pro-apoptotic BAD C/EBPβ. Phosphorylation renders inactive, phosphorylation C/EBPβ leads binding pro-caspases, thus inhibiting independently transcriptional this factor. Consistent with evidence phosphorylate diverse targets probably resulting from spatially distinct pools kinases, agents had additive effects on survival.