Protein Kinase Inhibitor γ Reciprocally Regulates Osteoblast and Adipocyte Differentiation by Downregulating Leukemia Inhibitory Factor. (December 2013)

• Record Type: Journal Article
• Authors: Chen, Xin; Hausman, Bryan S.; Luo, Guangbin; Zhou, Guang; Murakami, Shunichi; Rubin, Janet; Greenfield, Edward M.
• Is Part Of: Stem cells. Volume 31:Number 12(2013:Dec.)
• Page Start: 2789
• Page End: 2799
• Publication Date: 2013-12
• Subjects: Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1524
• Languages: English
• ISSNs: 1066-5099

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p>The protein kinase inhibitor (<italic>Pki</italic>) gene family inactivates nuclear protein kinase A (PKA) and terminates PKA‐induced gene expression. We previously showed that <italic>Pkig</italic> is the primary family member expressed in osteoblasts and that <italic>Pkig</italic> 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 <italic>Pkig</italic> regulate osteoblast differentiation. <italic>Pkig</italic> is the primary family member in murine embryonic fibroblasts (MEFs), murine marrow‐derived mesenchymal stem cells, and human mesenchymal stem cells. <italic>Pkig</italic> deletion increased forskolin‐dependent nuclear PKA activation and gene expression and <italic>Pkig</italic> 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 <italic>Pkig</italic> deletion or knockdown. <italic>Pkig</italic> deletion or knockdown also simultaneously increased osteogenesis and decreased adipogenesis in mixed osteogenic/adipogenic medium. <italic>Pkig</italic> deletion increased PKA‐induced expression of leukemia inhibitory factor (<italic>Lif</italic>) mRNA and LIF protein. LIF neutralizing antibodies inhibited the effects on osteogenesis and adipogenesis of either <italic>Pkig</italic> deletion in MEFs or PKIγ knockdown in both murine and human mesenchymal stem cells. Collectively, our results show that endogenous levels of <italic>Pkig</italic> reciprocally regulate osteoblast and adipocyte differentiation and that this reciprocal regulation is mediated in part by LIF. S<sc>tem</sc> C<sc>ells</sc><italic>2013;31:2789–2799</italic></p> </abstract>