A2B Adenosine Receptor Promotes Mesenchymal Stem Cell Differentiation to Osteoblasts and Bone Formation in Vivo

Carroll, Shannon H.; Wigner, Nathan A.; Kulkarni, Nitin; Johnston-Cox, Hillary; Gerstenfeld, Louis C.; Ravid, Katya

doi:10.1074/jbc.m112.344994

Cited by 139 publications

(154 citation statements)

References 54 publications

(59 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%

“…However, A 1 and A 2B receptor knockout mice are reported to display increases in the trabecular and/or cortical bone [23,30], whilst A 2A receptor knockout mice have decreased cortical and trabecular bone [33]. At Fig.…”

Section: Discussionmentioning

confidence: 97%

“…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]. Recently, it has also been reported that stimulation of the A 2A receptors can enhance bone regeneration [31].…”

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: Discussionmentioning

confidence: 97%

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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“…However, another study indicated that adenosine, acting via the A2B receptor, may increase the osteogenic differentiation of rat long bone mesenchymal stem cells (Gharibi et al, 2011). Furthermore, a synthetic A2B receptor agonist has been shown to increase bone formation, and osteoblasts from A2B receptor knockout mice display reduced activity in vitro (Carroll et al, 2012). Recently, it was reported that the adenosine generated by ecto-5'-nucleotidase (CD-73) was important in promoting osteoblast differentiation (Takedachi et al, 2012).…”

Section: P1 Receptor Signalling and Osteoblastsmentioning

confidence: 99%

The role of purinergic signalling in the musculoskeletal system

Orriss

2015

Autonomic Neuroscience

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“…Both of the papers use an in vivo KO mouse approach-(1) Takedachi et al [14] use a model where adenosine production is compromised and (2) Carroll et al [15] use a model where the A2B AR, previously identified to be important for osteoblast differentiation, is missing. It is interesting to note that Takedachi et al highlight that (1) CD73 expression is regulated by Wntbcatenin signalling [16], a known critical pathway in bone metabolism and (2) the hypoxia inducible factor-1a (HIF1a), a transcription factor reported to be important for bone regeneration and skeletal development also regulates CD73 expression.…”

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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A2B Adenosine Receptor Promotes Mesenchymal Stem Cell Differentiation to Osteoblasts and Bone Formation in Vivo

Cited by 139 publications

References 54 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

The role of purinergic signalling in the musculoskeletal system

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

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