An emerging role for adenosine and its receptors in bone homeostasis

Bone is continually being remodeled and defects in the processes involved lead to bone diseases. Many regulatory factors are known to influence remodeling but other mechanisms, hitherto unknown, may also be involved. Importantly, our understanding of these currently unknown mechanisms may lead to important new therapies for bone disease. It is accepted that purinergic signaling is involved in bone, and our knowledge of this area has increased significantly over the last 15 years, although most of the published work has studied the role of ATP and other signaling molecules via the P2 family of purinergic receptors. During the last few years, however, there has been increased interest within the bone field in the role of P1 receptors where adenosine is the primary signaling molecule. This review will bring together the current information available in relation to this expanding area of research

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

Osteoblasts and adipocytes differentiate from a common precursor cell, the mesenchymal stem cell (MSC). Adenosine is known to signal via four adenosine receptor subtypes, and significantly, recent findings indicate that these may play a role in MSC differentiation. We therefore investigated adenosine receptor expression and activation during the differentiation of MSCs to osteoblasts and adipocytes. The A2BR was dominant in MSCs, and its expression and activity were transiently upregulated at early stages of osteoblastic differentiation. Both activation and overexpression of A2BR induced the expression of osteoblast-related genes [Runx2 and alkaline phosphatase (ALP)], as well as ALP activity, and stimulation increased osteoblast mineralization. The expression of A2AR was upregulated during later stages of osteoblastic differentiation, when its activation stimulated ALP activity. Differentiation of MSCs to adipocytes was accompanied by significant increases in A1R and A2AR expression, and their activation was associated with increased adipogenesis. Enhanced A2AR expression was sufficient to promote expression of adipocyte-related genes (PPAR and C/EBP), and its activation resulted in increased adipocytic differentiation and lipid accumulation. In contrast, the A1R was involved mainly in lipogenic activity of adipocytes rather than in their differentiation. These results show that adenosine receptors are differentially expressed and involved in lineage-specific differentiation of MSCs. We conclude, therefore, that fruitful strategies for treating diseases associated with an imbalance in the differentiation and function of these lineages should include targeting adenosine receptor signal pathways. Specifically, these research avenues will be useful in preventing or treating conditions with insufficient bone or excessive adipocyte formation

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

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

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

The vital osteoclast: how is it regulated? [Editorial]

Bone is a rigid but dynamic organ. Once formed, it is continually broken down and reformed by the co-ordinated actions of osteoclasts (that mediate resorption) and osteoblasts (that mediate formation) on trabecular bone surfaces and in the Haversian systems of cortical bone. Any net change in bone mass therefore reflects a change in the balance between these two processes. If osteoclastic bone resorption exceeds the bone-forming capacity of osteoblasts, the result is osteoporosis, but if the opposite occurs the result is osteopetrosis. This remodelling occurs in focal and discrete packets – bone-remodelling units – throughout the skeleton. As the remodelling that occurs in each unit is geographically and chronologically separated from other units of remodelling, it is thought that activation of the sequence of cellular events responsible is locally controlled, probably by paracrine signalling in the bone microenvironment

Some aspects of androgen insensitivity

The clinical and endocrine features of the syndromes of androgen insensitivity which display a wide phenotypic spectrum are reviewed. A simple, dispersed whole cell assay to study androgen receptor binding in genital skin fibroblasts has been used to determine the pathogenesis of androgen insensitivity. Classification of the disorders based on in vitro studies does not show absolute concordance with the clinical sub-groups. Androgen-induced augmentation of basal specific binding is proposed as a possible functional test of androgen responsiveness in disorders such as partial androgen insensitivity, isolated hypospadias and micropenis. Understanding the cause of androgen insensitivity in many receptor-positive patients awaits identification and isolation of DNA probes for the X-linked gene locus for the androgen recepto

Some aspects of androgen insensitivity

The clinical and endocrine features of the syndromes of androgen insensitivity which display a wide phenotypic spectrum are reviewed. A simple, dispersed whole cell assay to study androgen receptor binding in genital skin fibroblasts has been used to determine the pathogenesis of androgen insensitivity. Classification of the disorders based on in vitro studies does not show absolute concordance with the clinical sub-groups. Androgen-induced augmentation of basal specific binding is proposed as a possible functional test of androgen responsiveness in disorders such as partial androgen insensitivity, isolated hypospadias and micropenis. Understanding the cause of androgen insensitivity in many receptor-positive patients awaits identification and isolation of DNA probes for the X-linked gene locus for the androgen recepto