Mechanisms and Clinical Consequences of Vascular Calcification

Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events, including myocardial infarction and stroke. Previously vascular calcification was thought to be a passive process which involved the deposition of calcium and phosphate in arteries and cardiac valves. However, recent studies have shown that vascular calcification is a highly regulated, cell-mediated process similar to bone formation. In this article, we outline the current understanding of key mechanisms governing vascular calcification and highlight the clinical consequences. By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health

Suppressor of cytokine signaling 2 (SOCS2) deletion protects bone health of mice with DSS induced inflammatory bowel disease.

Individuals with inflammatory bowel disease (IBD) often present with poor bone health. The development of targeted therapies for this bone loss requires a fuller understanding of the underlying cellular mechanisms. Although bone loss in IBD is multifactorial the altered sensitivity and secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in IBD is understood to be a critical contributing mechanism. The expression of suppressor of cytokine signaling 2 (SOCS2), a well-established negative regulator of GH signaling, is stimulated by pro-inflammatory cytokines. Therefore, it is likely that SOCS2 expression represents a critical mediator through which pro-inflammatory cytokines inhibit GH/IGF-1 signaling and decrease bone quality in IBD. Utilising the DSS model of colitis we have revealed that endogenously elevated GH function in the Socs2−/− mouse protects the skeleton from osteopenia. Micro-computed tomography assessment of DSS treated wild-type mice revealed a worsened trabecular architecture compared to control mice. Specifically, DSS treated WT mice had significantly decreased bone volume (BV/TV) (41%; p<0.05), trabecular thickness (16%; p<0.05), trabecular number (30%; p<0.05), and a resulting increase in trabecular separation (19%; <0.05). In comparison, the trabecular bone of Socs2 deficient mice was partially protected from the adverse effects of DSS. The reduction in a number of parameters including BV/TV (21%; p<0.05) was less, and no changes were observed in trabecular thickness or separation. This protected phenotype was unlikely to be a consequence of improved mucosal health in the DSS treated Socs2−/− mice but rather a result of unregulated GH signaling directly on bone. These studies indicate that the absence of SOCS2 is protective against bone loss typical of IBD. This study also provides an improved understanding of the relative effects of GH/IGF-1 on bone health in experimental colitis, information that is essential before these drugs are explored as bone protective agents in children and adults with IBD

Skeletal energy homeostasis:a paradigm of endocrine discovery

Throughout the last decade, significant developments in cellular, molecular and mouse models have revealed major endocrine functions of the skeleton. More recent studies have evolved the interplay between bone-specific hormones, the skeleton, marrow adipose tissue, muscle and the brain. This review focuses on literature from the last decade, addressing the endocrine regulation of global energy metabolism via the skeleton. In addition, we will highlight several recent studies that further our knowledge of new endocrine functions of some organs; explore remaining unanswered questions; and, finally, we will discuss future directions for this more complex era of bone biology research.</jats:p

A protective role for FGF-23 in local defence against disrupted arterial wall integrity?

Increasing interest is focusing on the role of the FGF-23/Klotho axis in mediating vascular calcification. However, the underpinning mechanisms have yet to be fully elucidated. Murine VSMCs were cultured in calcifying medium for a 21d period. FGF-23 mRNA expression was significantly up-regulated by 7d (1.63 fold; P<0.001), with a concomitant increase in protein expression. mRNA and protein expression of both FGFR1 and Klotho were confirmed. Increased FGF-23 and Klotho protein expression was also observed in the calcified media of Enpp1(−/−) mouse aortic tissue. Reduced calcium deposition was observed in calcifying VSMCs cultured with recombinant FGF-23 (10ng/ml; 28.1% decrease; P<0.01). Calcifying VSMCs treated with PD173074, an inhibitor of FGFR1 and FGFR3, showed significantly increased calcification (50nM; 87.8% increase; P<0.001). FGF-23 exposure induced phosphorylation of ERK1/2. Treatment with FGF-23 in combination with PD98059, an ERK1/2 inhibitor, significantly increased VSMC calcification (10μM; 41.3% increase; P<0.01). Use of FGF-23 may represent a novel therapeutic strategy for inhibiting vascular calcification

A tale of two cities: restoring water services in Kabul and Monrovia

Kabul and Monrovia, the respective capitals of Afghanistan and Liberia, have recently emerged from long-lasting armed conflicts. In both cities, a large number of organisations took part in emergency water supply provision and later in the rehabilitation of water systems. Based on field research, this paper establishes a parallel between the operations carried out in the two settings, highlighting similarities and analysing the two most common strategies. The first strategy involves international financial institutions, which fund large-scale projects focusing on infrastructural rehabilitation and on the institutional development of the water utility, sometimes envisaging private-sector participation. The second strategy involves humanitarian agencies, which run community-based projects, in most cases independently of the water utilities, and targeting low-income areas. Neither of these approaches manages to combine sustainability and universal service. The paper assesses their respective strengths and weaknesses and suggests ways of improving the quality of assistance provided

Self-Prioritization Reconsidered : Scrutinizing Three Claims

Open Access via the Sage R&P AgreementPeer reviewedPublisher PD

Judging Me and You : Task Design Modulates Self-Prioritization

Peer reviewedPublisher PD

The temporal profile of self-prioritization

Peer reviewe

Learning about me and you : Only deterministic stimulus associations elicit self-prioritization

Open Access via the Elsevier agreement Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Peer reviewedPublisher PD

ENPP1 in the Regulation of Mineralization and Beyond

ENPP1 is well known for its role in regulating skeletal and soft tissue mineralization. It primarily exerts its function through the generation of pyrophosphate, a key inhibitor of hydroxyapatite formation. Several previous studies have suggested that ENPP1 also contributes to a range of human diseases including diabetes, cancer, cardiovascular disease, and osteoarthritis. In this review, we summarize the pathological roles of ENPP1 in mineralization and these soft tissue disorders. We also discuss the underlying mechanisms through which ENPP1 exerts its pathological effects. A fuller understanding of the pathways through which ENPP1 acts may help to develop novel therapeutic strategies for these commonly diagnosed morbidities.</p