Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes

Gharibi, Borzo; Abraham, Anju; Ham, Jack; Evans, Bronwen Alice James

doi:10.1002/jbmr.424

Cited by 137 publications

(165 citation statements)

References 46 publications

(53 reference statements)

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“…The work presented here showed no effects of adenosine, 2-chloroadenosine, GR79236 or BAY606583 on calvarialderived osteoblasts; this is in broad agreement with previous studies which showed exogenous adenosine had no effect on cultured rat osteoblasts [11,29]. However, our results are at variance with several studies which found that adenosine or adenosine analogues, acting via the A 2A or A 2B receptors, stimulate the differentiation and function of human and rodent bone marrow osteoblasts and promote bone regeneration [24,30,31,40]. Our data also do not concur with the reported inhibitory effects of adenosine analogues, acting via A 1 or A 2A receptors, on the differentiation of rodent osteoblast-like cells [41] or human osteoblasts [40].…”

Section: Discussionsupporting

confidence: 92%

“…Both osteoblasts and osteoclasts have been reported to express all four P1 receptor subtypes [23][24][25][26][27]. However, the actions of extracellular adenosine on bone cells appear to be somewhat less clear-cut than those of ATP.…”

Section: Introductionmentioning

confidence: 99%

“…Two independent groups failed to find an effect of adenosine on the formation of mineralised bone nodules by rat calvarial osteoblasts [11,29]. However, a more recent study indicated that adenosine, acting via the A 2B receptor, may increase the osteogenic differentiation of rat long bone mesenchymal stem cells [24]. In addition, a synthetic A 2B receptor agonist has been shown to increase bone formation, and bone marrow osteoblasts from A 2B receptor knockout mice display reduced levels of bone formation [30].…”

Section: Introductionmentioning

confidence: 99%

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Lack of effect of adenosine on the function of rodent osteoblasts and osteoclasts in vitro

Hajjawi

Patel

Corcelli

et al. 2016

Purinergic Signalling

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Extracellular ATP, signalling through P2 receptors, exerts well-documented effects on bone cells, inhibiting mineral deposition by osteoblasts and stimulating the formation and resorptive activity of osteoclasts. The aims of this study were to determine the potential osteotropic effects of adenosine, the hydrolysis product of ATP, on primary bone cells in vitro. We determined the effect of exogenous adenosine on (1) the growth, alkaline phosphatase (TNAP) activity and bone-forming ability of osteoblasts derived from the calvariae of neonatal rats and mice and the marrow of juvenile rats and (2) the formation and resorptive activity of osteoclasts from juvenile mouse marrow. Reverse transcription polymerase chain reaction (RT-PCR) analysis showed marked differences in the expression of P1 receptors in osteoblasts from different sources. Whilst mRNA for the A 1 and A 2B receptors was expressed by all primary osteoblasts, A 2A receptor expression was limited to rat bone marrow and mouse calvarial osteoblasts and the A 3 receptor to rat bone marrow osteoblasts. We found that adenosine had no detectable effects on cell growth, TNAP activity or bone formation by rodent osteoblasts in vitro. The analogue 2-chloroadenosine, which is hydrolysed more slowly than adenosine, had no effects on rat or mouse calvarial osteoblasts but increased TNAP activity and bone formation by rat bone marrow osteoblasts by 30-50 % at a concentration of 1 μM. Osteoclasts were found to express the A 2A , A 2B and A 3 receptors; however, neither adenosine (≤100 μM) nor 2-chloroadenosine (≤10 μM) had any effect on the formation or resorptive activity of mouse osteoclasts in vitro. These results suggest that adenosine, unlike ATP, is not a major signalling molecule in the bone.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lack of effect of adenosine on the function of rodent osteoblasts and osteoclasts in vitro

Hajjawi

Patel

Corcelli

et al. 2016

Purinergic Signalling

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“…cAMP has been shown to induce abnormal calcification of vascular smooth muscle cells via a mechanism involving reduction in extracellular PP i accumulation. (60,61) In addition, activation of the P2X7 subtype of ATP receptors promotes bone formation and mineralization. (59,62) Taken together, our data suggest that disruption of adenosine signaling and PP i metabolism in ENT1 -/-mice is associated with disease onset and progression.…”

Section: Discussionmentioning

confidence: 99%

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Warraich

Bone

Quinonez

et al. 2012

Journal of Bone and Mineral Research

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Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory spondyloarthropathy, characterized by ectopic calcification of spinal tissues. Symptoms include spine pain and stiffness, and in severe cases dysphagia and spinal cord compression. The etiology of DISH is unknown and there are no specific treatments. Recent studies have suggested a role for purine metabolism in the regulation of biomineralization. Equilibrative nucleoside transporter 1 (ENT1) transfers hydrophilic nucleosides, such as adenosine, across the plasma membrane. In mice lacking ENT1, we observed the development of calcified lesions resembling DISH. By 12 months of age, ENT1 -/-mice exhibited signs of spine stiffness, hind limb dysfunction, and paralysis. Micro-computed tomography (mCT) revealed ectopic mineralization of paraspinal tissues in the cervical-thoracic region at 2 months of age, which extended to the lumbar and caudal regions with advancing age. Energy-dispersive X-ray microanalysis of lesions revealed a high content of calcium and phosphorus with a ratio similar to that of cortical bone. At 12 months of age, histological examination of ENT1 -/-mice revealed large, irregular accumulations of eosinophilic material in paraspinal ligaments and entheses, intervertebral discs, and sternocostal articulations. There was no evidence of mineralization in appendicular joints or blood vessels, indicating specificity for the axial skeleton. Plasma adenosine levels were significantly greater in ENT1 -/-mice than in wild-type, consistent with loss of ENT1-a primary adenosine uptake pathway. There was a significant reduction in the expression of Enpp1, Ank, and Alpl in intervertebral discs from ENT1 -/-mice compared to wild-type mice. Elevated plasma levels of inorganic pyrophosphate in ENT1 -/-mice indicated generalized disruption of pyrophosphate homeostasis. This is the first report of a role for ENT1 in regulating the calcification of soft tissues. Moreover, ENT1 -/-mice may be a useful model for investigating pathogenesis and evaluating therapeutics for the prevention of mineralization in DISH and related disorders. ß

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“…This work included studies from the A2A AR KO mouse. Further insights into the role of adenosine and its receptors in the modulation of mesenchymal stem cell differentiation have come from two in vitro cell based studies published last year [6,7].…”

Section: Commentarymentioning

confidence: 99%

Does adenosine play a role in bone formation, resorption and repair?

Evans

2012

Purinergic Signalling

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There has been increasing interest recently in the role purinergic signalling in the physiology and pathophysiology of musculoskeletal tissues, especially bone. Whereas the role of ATP in bone metabolism [1,2] has been revealed to some extent and quite a few papers have been published in this respect, functions of its metabolite adenosine are not understood. Bone remodelling is a continuous, life-long process that maintains skeletal integrity. It is orchestrated by the three bone cell types (osteoblasts, osteoclasts and osteocytes), and impairments eventually result in diseases such as osteoporosis. Although there is much insight into the systems that maintain healthy bone, there is still a need to develop new therapies. The hypothesis that the adenosine signalling pathways might provide new targets for bone disease has gained further momentum recently with the publication of the following two papers that are commented on by Bronwen A. J. Evans of Cardiff University. Interestingly enough, the first article deals with findings obtained using CD73 null mice, that have also been the subject of another recently published Highlight [3] that focused on the role of local and systemic adenosine in modulation of antitumour responses in vivo. Here, CD73 null mice have been exploited to unveil a potential role of adenosine in osteoblast differentiation. In the second commented article, by using adenosine A2B receptor knockout mice, this receptor is identified as a main target for adenosine in promoting the differentiation of mesenchymal stem cell to osteoblasts. Article summaryM. Takedachi and colleagues hypothesized that CD73 may be involved in regulating function of the bone forming cell (osteoblast) through modulating nucleotide metabolism and generating extracellular adenosine that can activate adenosine receptors (ARs). To address this hypothesis, they asked whether CD73 functionally regulates bone metabolism in vivo by characterizing the bone phenotype of cd73−/− mice. In addition, they investigated the involvement of CD73 and AR signalling in osteoblast differentiation in vitro.Micro-computed tomography (μCT) showed that 13 week old male mice had osteopenia, and that this was due to reduced trabecular bone volume, decreased trabecular number and thickness, and increased trabecular separation in cd73−/− mice when compared to wild-type controls. Subsequent work measuring biochemical markers of bone formation showed that osteocalcin (bone formation marker) was decreased in cd73−/− mice whereas bone resorption markers (TRAP5b and fragments of type I collagen) were comparable to wild-type animals. The association of the osteoblast to the impared bone phenotype seen in cd73−/− mice was further substantiated using quantitative RT-PCR. These

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Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes

Cited by 137 publications

References 46 publications

Lack of effect of adenosine on the function of rodent osteoblasts and osteoclasts in vitro

Lack of effect of adenosine on the function of rodent osteoblasts and osteoclasts in vitro

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Does adenosine play a role in bone formation, resorption and repair?

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