Parathyroid hormone (1-34) counteracts the suppression of interleukin-11 expression by glucocorticoid in murine osteoblasts: A possible mechanism for stimulating osteoblast differentiation against glucocorticoid excess

Abstract

Glucocorticoid (GC) excess causes a rapid loss of bone with a reduction in bone formation. Intermittent PTH(1-34) administration stimulatesboneformationandcounteracts the inhibition ofboneformation by GC excess. We have previously demonstrated that mechanical strain enhances interleukin (IL)-11 gene transcription by a rapid induction of δFosB expression and protein kinase C (PKC)-α-mediated phosphorylation of phosphorylated mothers against decapentaplegic (Smad)-1. Because IL-11 suppresses the expression of dickkopf-1 and -2 and stimulates Wnt signaling, IL-11 appears to mediate at least a part of the effect of mechanical strain on osteoblast differentiation and bone formation. The present studywasundertakentoexaminetheeffect of PTH(1-34)andGCsonIL-11 expression inmurine primary osteoblasts (mPOBs). PTH(1-34) treatment of mPOBs enhanced IL-11 expression in a time- and dose-dependent manner. PTH(1-34) also stimulated δFosB expression and Smad1 phosphorylation, which cooperatively stimulated IL-11 gene transcription. PTH(1-34)-induced Smad1 phosphorylation was mediated via PKCσ and was abrogated in mPOBs from PKCα knockout mice. Dexamethasone suppressed IL-11 gene transcription enhanced by PTH(1-34) without affecting δFosB expression or Smad1 phosphorylation, and dexamethasone-GC receptor complex was bound to JunD, which forms heterodimers withδFosB. High doses of PTH(1-34) counteracted the effect of dexamethasoneonapoptosis of mPOBs, which was blunted by neutralizing anti-IL-11 antibody or IL-11 small interfering RNA. These results demonstrate that PTH(1-34) and GCs interact to regulate IL-11 expression in parallel with osteoblast differentiation and apoptosis and suggest that PTH(1-34) and dexamethasone may regulate osteoblast differentiation and apoptosis via their effect on IL-11 expression. Copyright © 2013 by The Endocrine Society.