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

Lilian Plotkin, J. Ignacio Aguirre, Stavroula Kousteni, Stavros C. Manolagas, Teresita Bellido

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Abstract

Both estrogens and bisphosphonates attenuate osteocyte apoptosis by activating the extracellular signal-regulated kinases (ERKs). However, whereas estrogens activate ERKs via an extranuclear function of the estrogen receptor, bisphosphonates do so by opening connexin 43 hemichannels. Here, we demonstrated that the signaling events downstream of ERKs induced by these two stimuli are also distinct. Inhibition of osteocyte apoptosis by estrogens requires nuclear accumulation of ERKs and activation of downstream transcription factors. On the other hand, anti-apoptosis induced by bisphosphonatesrequires neithertranscription nor ERK-dependent transcription factors. Instead, the effect of bisphosphonates is abolished when ERKs are restricted to the nucleus by blocking CRM1/exportin1-mediated nuclear protein export or by expressing nuclear-anchored ERKs, but it is unaffected in cells expressing cytoplasmic-anchored ERKs. Connexin 43/ERK-mediated anti-apoptosis induced by bisphosphonates requires the kinase activity of the cytoplasmic target of ERKs, p90RSK, which in turn phosphorylates the proapoptotic protein BAD and C/EBPβ. Phosphorylation of BAD renders it inactive, whereas phosphorylation of C/EBPβ leads to binding of pro-caspases, thus inhibiting apoptosis independently of the transcriptional activity of this transcription factor. Consistent with the evidence that estrogens and bisphosphonates phosphorylate diverse targets of ERKs, probably resulting from activation of spatially distinct pools of these kinases, the two agents had additive effects on osteocyte survival.

Original languageEnglish (US)
Pages (from-to)7317-7325
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number8
DOIs
StatePublished - Feb 25 2005
Externally publishedYes

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Osteocytes
Extracellular Signal-Regulated MAP Kinases
Diphosphonates
Estrogens
Chemical activation
Apoptosis
Connexin 43
Phosphorylation
Transcription Factors
Phosphotransferases
CCAAT-Enhancer-Binding Proteins
Cell Nucleus Active Transport
Caspases
Nuclear Proteins
Estrogen Receptors
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. / Plotkin, Lilian; Aguirre, J. Ignacio; Kousteni, Stavroula; Manolagas, Stavros C.; Bellido, Teresita.

In: Journal of Biological Chemistry, Vol. 280, No. 8, 25.02.2005, p. 7317-7325.

Research output: Contribution to journalArticle

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