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A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo.

ABSTRACT: The differentiation of osteoblasts from their precursors, mesenchymal stem cells, is an important component of bone homeostasis as well as fracture healing. The A2B adenosine receptor (A2BAR) is a Gα(s)/α(q)-protein-coupled receptor that signals via cAMP. cAMP-mediated signaling has been demonstrated to regulate the differentiation of mesenchymal stem cells (MSCs) into various skeletal tissue lineages. Here, we studied the role of this receptor in the differentiation of MSCs to osteoblasts. In vitro differentiation of bone marrow-derived MSCs from A2BAR KO mice resulted in lower expression of osteoblast differentiation transcription factors and the development of fewer mineralized nodules, as compared with WT mice. The mechanism of effect involves, at least partially, cAMP as indicated by experiments involving activation of the A2BAR or addition of a cAMP analog during differentiation. Intriguingly, in vivo, microcomputed tomography analysis of adult femurs showed lower bone density in A2BAR KO mice as compared with WT. Furthermore, A2BAR KO mice display a delay in normal fracture physiology with lower expression of osteoblast differentiation genes. Thus, our study identified the A2BAR as a new regulator of osteoblast differentiation, bone formation, and fracture repair.

SUBMITTER: Carroll SH

PROVIDER: S-EPMC3346096 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo.

Carroll Shannon H SH Wigner Nathan A NA Kulkarni Nitin N Johnston-Cox Hillary H Gerstenfeld Louis C LC Ravid Katya K

The Journal of biological chemistry 20120308 19

The differentiation of osteoblasts from their precursors, mesenchymal stem cells, is an important component of bone homeostasis as well as fracture healing. The A2B adenosine receptor (A2BAR) is a Gα(s)/α(q)-protein-coupled receptor that signals via cAMP. cAMP-mediated signaling has been demonstrated to regulate the differentiation of mesenchymal stem cells (MSCs) into various skeletal tissue lineages. Here, we studied the role of this receptor in the differentiation of MSCs to osteoblasts. In v ...[more]

PMID: 22403399

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Project description:PurposeIn osteoporosis, the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) is disrupted. The osteogenic differentiation of bone marrow MSCs (BMSCs) is important for improving osteoporosis. The aim of this study was to explore the role and molecular mechanism of miR-210 in the balance of osteogenic/adipogenic differentiation of BMSCs in postmenopausal osteoporosis.MethodsPostmenopausal osteoporosis rat models were constructed by ovariectomy (OVX). BMSCs were isolated from the femur in rats of Sham and OVX groups. MiR-210 was overexpressed and suppressed by miR-210 mimics and inhibitor, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative mRNA expression of miR-210, ephrin type-A receptor 2 (EPHA2), alkaline phosphatase (ALP), osterix (OSX), osteocalcin (Bglap), Runt-related transcription factor 2 (Runx2), peroxisome proliferator activated receptor gamma, and fatty acid binding protein 4 (FABP4) in each group of rat femoral tissues or BMSCs. Western blot was applied to detect the protein expression level of EPHA2 in rat femoral tissues and cells. Alizarin red S staining and oil red O staining were performed to assess the osteogenic and adipogenic differentiation of BMSCs, respectively. In addition, the targeting relationship between miR-210 and EPHA2 was verified by a dual luciferase gene reporter assay.ResultsThe expression of miR-210 was significantly reduced in femoral tissues and BMSCs of OVX rats, and its low expression was associated with reduced bone formation. The osteogenic differentiation was enhanced in OVX rats treated with miR-210 mimic. Overexpression of miR-210 in transfected BMSCs was also found to significantly promote osteogenic differentiation and even inhibit adipogenic differentiation in BMSCs, while knockdown of miR-210 did the opposite. Further mechanistic studies showed that miR-210 could target and inhibit the expression of EPHA2 in BMSCs, thus promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs.ConclusionMiR-210 promotes osteogenic differentiation and inhibits adipogenic differentiation of BMSCs by down-regulating EPHA2 expression. As it plays an important role in the osteogenic/adipogenic differentiation of osteoporosis, miR-210 can serve as a potential miRNA biomarker for osteoporosis.

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A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo.

Publications

A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo.

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