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

Abstract

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

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

“…In this regard, recent advances point to a critical role for purine metabolism and signaling in the regulation of biomineralization and in diseases associated with either insufficient or ectopic mineralization. (25)(26)(27)(28)(29)(30) Once released by the cell, extracellular adenosine triphosphate (ATP) is sequentially metabolized by cell-surface enzymes, leading first to the production of PP i and adenosine monophosphate (AMP), which in turn are converted to inorganic phosphate and adenosine. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is responsible for the first step in this process, and the release of PP i has been shown to inhibit ectopic calcification in soft tissues.…”

“…(18) Recent advances point to a critical role for purine metabolism in the regulation of biomineralization in diseases associated with either insufficient or ectopic mineralization. (25)(26)(27)(28)(29)(30) For example, mutations in the gene encoding ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) have been associated with hypermineralization disorders. (25,26) Moreover, a recent study has linked ectopic arterial and joint calcifications with loss of ecto-5 0 -nucleotidase (5 0 NTD) function leading to decreased levels of extracellular adenosine.…”

Adult mesenchymal stem cells: is there a role for purine receptors in their osteogenic differentiation?

“…A2BR activation enhanced cell osteogenic differentiation by upregulating the expression of typical osteogenic markers like Runx2. Accordingly, BMSCs from A2BR knockout mice showed a reduced osteogenic potential and the same knockout animals exhibited a lower bone density and a delayed fracture repair [204]. Stimulation of A2BR also attenuated bone loss in ovariectomized mice, highlighting the potential of A2BR as a target to treat osteoporosis consequent to estrogen deficiency [205].…”

Control Release of Adenosine Potentiate Osteogenic Differentiation within a Bone Integrative EGCG-g-NOCC/Collagen Composite Scaffold toward Guided Bone Regeneration in a Critical-Sized Calvarial Defect

“…These receptors are recently identified as modulators of osteoblast/osteoclast differentiation, their functions, and overall bone homeostasis. 28,60 Before using in in vivo conditions, the role of adenosine was established as a potential pro-osteogenic agent for bone marrow derived MSCs ex vivo. Adenosine was found cytocompatible with BMSCs for up to 7 days.…”