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

The protein kinase inhibitor (Pki) gene family inactivates nuclear protein kinase A and terminates 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 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 duanyu1529 activation and gene expression and Pkig deletion or knockdown increased osteoblast differentiation. duanyu1529 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 duanyu1529 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 duanyu1529-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.

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