Protein kinase inhibitor γ reciprocally regulates osteoblast and adipocyte differentiation by downregulating leukemia inhibitory factor

Xin Chen, Bryan S. Hausman, Guangbin Luo, Guang Zhou, Shunichi Murakami, Janet Rubin, Edward M. Greenfield

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The protein kinase inhibitor (Pki) gene family inactivates nuclear protein kinase A (PKA) and terminates PKAinduced gene expression. We previously showed that Pkig is the primary family member expressed in osteoblasts and that Pkig knockdown increases the effects of parathyroid hormone and isoproterenol on PKA activation, gene expression, and inhibition of apoptosis. Here, we determined whether endogenous levels of Pkig regulate osteoblast differentiation. Pkig is the primary family member in murine embryonic fibroblasts (MEFs), murine marrowderived mesenchymal stem cells, and human mesenchymal stem cells. Pkig deletion increased forskolin-dependent nuclear PKA activation and gene expression and Pkig deletion or knockdown increased osteoblast differentiation. PKA signaling is known to stimulate adipogenesis; however, adipogenesis and osteogenesis are often reciprocally regulated. We found that the reciprocal regulation predominates over the direct effects of PKA since adipogenesis was decreased by Pkig deletion or knockdown. Pkig deletion or knockdown also simultaneously increased osteogenesis and decreased adipogenesis in mixed osteogenic/ adipogenic medium. Pkig deletion increased PKAinduced expression of leukemia inhibitory factor (Lif) mRNA and LIF protein. LIF neutralizing antibodies inhibited the effects on osteogenesis and adipogenesis of either Pkig deletion in MEFs or PKIγ knockdown in both murine and human mesenchymal stem cells. Collectively, our results show that endogenous levels of Pkig reciprocally regulate osteoblast and adipocyte differentiation and that this reciprocal regulation is mediated in part by LIF.

Original languageEnglish (US)
Pages (from-to)2789-2799
Number of pages11
JournalStem Cells
Volume31
Issue number12
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

Keywords

  • Adipogenesis
  • Leukemia inhibitory factor
  • Mesenchymal stem cell
  • Osteogenesis
  • Protein kinase inhibitor

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Protein kinase inhibitor γ reciprocally regulates osteoblast and adipocyte differentiation by downregulating leukemia inhibitory factor'. Together they form a unique fingerprint.

  • Cite this