Sclerostin and DKK1 : new players in renal bone and vascular disease
TL;DR: Caution is however warranted as sclerostin not only opposes mineralization in the bone but possibly also in the vasculature, as additional studies are required to define determinants of Wnt inhibitors in CKD and to evaluate the efficacy and safety of recently introduced pharmaceuticals targeting these inhibitors.
About: This article is published in Kidney International.The article was published on 2015-08-01 and is currently open access. It has received 113 citations till now. The article focuses on the topics: Sclerostin & Bone resorption.
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TL;DR: A systems biology approach to CKD using omics techniques will hopefully enable in-depth study of the pathophysiology of this systemic disease, and has the potential to unravel critical pathways that can be targeted for CKD prevention and therapy.
Abstract: The accurate definition and staging of chronic kidney disease (CKD) is one of the major achievements of modern nephrology. Intensive research is now being undertaken to unravel the risk factors and pathophysiologic underpinnings of this disease. In particular, the relationships between the kidney and other organs have been comprehensively investigated in experimental and clinical studies in the last two decades. Owing to technological and analytical limitations, these links have been studied with a reductionist approach focusing on two organs at a time, such as the heart and the kidney or the bone and the kidney. Here, we discuss studies that highlight the complex and systemic nature of CKD. Energy balance, innate immunity and neuroendocrine signalling are highly integrated biological phenomena. The diseased kidney disrupts such integration and generates a high-risk phenotype with a clinical profile encompassing inflammation, protein-energy wasting, altered function of the autonomic and central nervous systems and cardiopulmonary, vascular and bone diseases. A systems biology approach to CKD using omics techniques will hopefully enable in-depth study of the pathophysiology of this systemic disease, and has the potential to unravel critical pathways that can be targeted for CKD prevention and therapy.
236 citations
TL;DR: Evidence is provided that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients, and FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease.
137 citations
TL;DR: It is demonstrated that circulating renal repair and injury factors are causal of the CKD-MBD and CKD associated cardiovascular disease.
128 citations
TL;DR: The data suggest that uncontrolled hyperparathyroidism is not the key determinant of calciphylaxis, and will help substantially to initiate a large-scale multinational CUA registry.
Abstract: Background Calcific uraemic arteriolopathy (CUA, calciphylaxis) is a rare disease predominantly in dialysis patients and associated with high mortality. Painful skin ulcerations and calcification of cutaneous arterioles characterize calciphylaxis. Methods We established an observational, Internet-based registry allowing online notification for all German CUA cases. The registry recorded data about patient characteristics, biochemistry and therapies. Blood samples were stored in a central biobank. Results Between 2006 and 2015, 253 CUA patients were recorded: median age 70 [interquartile range (IQR) 61-76] years, 60% females and 86% ( n = 207) dialysis patients, translating into an estimated annual incidence rate of 0.04% in German dialysis patients. Fifty-two per cent received vitamin K antagonists (VKAs) prior to CUA. Skin lesions were localized in 71% on the legs or gluteal region. In dialysis CUA patients median total serum calcium was 2.20 (IQR 2.06-2.37) mmol/L, phosphorus 1.67 (IQR 1.35-2.03) mmol/L, intact parathyroid hormone 147 (IQR 72-276) pg/mL and fetuin-A 0.21 (IQR 0.16-0.26) g/L (normal range 0.35-0.95). Median sclerostin, osteoprotegerin, TRAP5b, bone-specific alkaline phosphatase and c-terminal FGF23 levels were all elevated. The most frequently recorded therapeutic procedures in dialysis CUA patients were as follows: wound debridement (29% of cases), stopping VKA (25%), lowering calcium supply (24%), sodium thiosulphate (22%), application of vitamin K (18%), increase of dialysis duration/frequency (17%) and stoping active vitamin D (16%). Conclusions Approximately 50% of CUA patients used VKA. Our data suggest that uncontrolled hyperparathyroidism is not the key determinant of calciphylaxis. Therapeutic strategies were heterogeneous. The experience of the German registry will help substantially to initiate a large-scale multinational CUA registry.
113 citations
Cites background from "Sclerostin and DKK1 : new players i..."
...The potential role of sclerostin as a marker or mediator of vascular calcification is a matter of ongoing debate [10]....
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TL;DR: While osteoblast exposure to parathyroid hormone suppressed the expression of Wnt inhibitors, FGF23 directly inhibited the osteoblastic Wnt pathway through a soluble Klotho/MAPK-mediated process that required Dkk1 induction, providing a novel autocrine/paracrine mechanism for the adverse impact of high F GF23 levels on bone in chronic kidney disease.
109 citations
References
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TL;DR: Current understanding of the mechanisms by which WNT signalng regulates bone homeostasis is reviewed, finding the pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture.
Abstract: Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
1,606 citations
TL;DR: In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption.
Abstract: Background Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. Methods In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of −2.0 or less at the lumbar spine, total hip, or femoral neck and −3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator — oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage ch...
946 citations
TL;DR: In vivo evidence is provided for the first time to support the concept that osteocytes secrete sclerostin after they become embedded in a mineralized matrix to limit further bone formation by osteoblasts and propose that sclerOSTin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces.
Abstract: Osteocytes are the most abundant cells in bone and are ideally located to influence bone turnover through their syncytial relationship with surface bone cells. Osteocyte-derived signals have remained largely enigmatic, but it was recently reported that human osteocytes secrete sclerostin, an inhibitor of bone formation. Absent sclerostin protein results in the high bone mass clinical disorder sclerosteosis. Here we report that within adult iliac bone, newly embedded osteocytes were negative for sclerostin staining but became positive at or after primary mineralization. The majority of mature osteocytes in mineralized cortical and cancellous bone was positive for sclerostin with diffuse staining along dendrites in the osteocyte canaliculi. These findings provide for the first time in vivo evidence to support the concept that osteocytes secrete sclerostin after they become embedded in a mineralized matrix to limit further bone formation by osteoblasts. Sclerostin did not appear to influence the formation of osteocytes. We propose that sclerostin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces. In doing so, sclerostin may act as a key inhibitory signal governing skeletal microarchitecture.
898 citations
TL;DR: Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals, which is characteristic of Wnt signaling.
Abstract: In diabetic LDLR –/– mice, an ectopic BMP2-Msx2 gene regulatory program is upregulated in association with vascular calcification. We verified the procalcific actions of aortic Msx2 expression in vivo. CMV-Msx2 transgenic (CMV-Msx2Tg + ) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates. On high-fat diets, CMV-Msx2Tg + mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media. This corresponded to regions of Msx2 immunoreactivity in adjacent adventitial myofibroblasts, suggesting a potential paracrine osteogenic signal. To better understand Msx2-regulated calcification, we studied actions in 10T1/2 cells. We found that conditioned media from Msx2-transduced 10T1/2 cells (Msx2-CM) is both pro-osteogenic and adipostatic; these features are characteristic of Wnt signaling. Msx2-CM stimulated Wnt-dependent TCF/LEF transcription, and Msx2-transduced cells exhibited increased nuclear β-catenin localization with concomitant alkaline phosphatase induction. Msx2 upregulated Wnt3a and Wnt7a but downregulated expression of the canonical inhibitor Dkk1. Dkk1 treatment reversed osteogenic and adipostatic actions of Msx2. Teriparatide, a PTH1R agonist that inhibits murine vascular calcification, suppressed vascular BMP2-Msx2-Wnt signaling. Analyses of CMV-Msx2Tg + mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts; moreover, TOPGAL + (Wnt reporter); CMV-Msx2Tg + mice exhibited augmented aortic LacZ expression. Thus, Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals.
421 citations
TL;DR: The results suggest that greater selectivity in prescribing several classes of psychoactive drugs and more efficient treatment of secondary hyperparathyroidism may help reduce the burden of fractures in HD patients.
386 citations