Cyclic AMP signaling in bone marrow stromal cells has reciprocal effects on the ability of mesenchymal stem cells to differentiate into mature osteoblasts versus mature adipocytes

Richard Kao,Robert Nissenson,Weidar Lu,Alyssa Louie

doi:10.1007/s12020-012-9717-9

Abstract

Stimulatory G protein-mediated cAMP signaling is intimately involved in skeletal homeostasis. However, limited information is available on the role of the cAMP signaling in regulating the differentiation of mesenchymal stem cells into mature osteoblasts and adipocytes. To investigate this, we treated primary mouse bone marrow stromal cells (BMSCs) with forskolin to stimulate cAMP signaling and determined the effect on osteoblast and adipocyte differentiation. Exposure of differentiating osteoblasts to forskolin markedly inhibited progression to the late stages of osteoblast differentiation, and this effect was replicated by continuous exposure to PTH. Strikingly, forskolin activation of cAMP signaling in BMSCs conditioned mesenchymal stem cells (MSCs) to undergo increased osteogenic differentiation and decreased adipogenic differentiation. PTH treatment of BMSCs also enhanced subsequent osteogenesis, but promoted an increased adipogenesis as well. Thus, activation of cAMP signaling alters the lineage commitment of MSCs, favoring osteogenesis at the expense of adipogenesis.

Highlights

Fibrous dysplasia (FD, OMIM 174800) of bone is one of the manifestations of the McCune–Albright syndrome
To determine whether the effects of Parathyroid hormone (PTH) on differentiating osteoblasts were exerted through the Cyclic AMP (cAMP)/PKA pathway, we pharmacologically stimulated cAMP signaling using an activator of adenylate cyclase, forskolin
Total alkaline phosphatase (ALP) activity in culture was not affected (Fig. 3d), similar to what was observed in osteoblast cultures that were treated with PTH continuously from day 5 to day 23

Summary

Introduction

Fibrous dysplasia (FD, OMIM 174800) of bone is one of the manifestations of the McCune–Albright syndrome. Patients with McCune–Albright syndrome have activating missense mutations in GNAS, the gene encoding the a subunit of Gs [1,2,3]. These mutations have been demonstrated in various tissues, including bones [3,4,5] and samples from the monostotic form of fibrous dysplasia [6, 7]. Conditional deletion of the a subunit of Gs in osteoblast lineage cells resulted in reduced trabecular bone formation [10]. Alteration of Gs and Gi signallings in osteoblast lineage cells was able to generate striking, but opposite effects on skeletal tissues

Methods

Results

Conclusion