Protein Kinase Inhibitor γ Reciprocally Regulates Osteoblast and Adipocyte Differentiation by Downregulating Leukemia Inhibitory Factor

Author:

Chen Xin1,Hausman Bryan S.1,Luo Guangbin2,Zhou Guang12,Murakami Shunichi123,Rubin Janet4,Greenfield Edward M.135

Affiliation:

1. Department of Orthopaedics University of North Carolina, Chapel Hill, North Carolina, USA

2. Department of Genetics and Genome Sciences University of North Carolina, Chapel Hill, North Carolina, USA

3. Center for Regenerative Medicine School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

4. Department of Medicine University of North Carolina, Chapel Hill, North Carolina, USA

5. Department of Pathology School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

Abstract

Abstract The protein kinase inhibitor (Pki) gene family inactivates nuclear protein kinase A (PKA) and terminates PKA-induced 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 marrow-derived 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 PKA-induced 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. Stem Cells  2013;31:2789–2799

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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