Sclerostin and DKK1: new players in renal bone and vascular disease

Evenepoel, Pieter; D’Haese, Patrick C.; Brandenburg, Vincent

doi:10.1038/ki.2015.156

Cited by 130 publications

(94 citation statements)

References 53 publications

(99 reference statements)

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“…Another Wnt inhibitor whose circulating levels are increased in CKD and considered an important CKD-MBD factor is sclerostin 40–42 , a critical regulator of bone mass 43–46 . Sclerostin is considered an osteocyte specific protein 47–52 .…”

Section: Recent Advances In the Pathogenesis Of The Ckd-mbdmentioning

confidence: 99%

The chronic kidney disease — Mineral bone disorder (CKD-MBD): Advances in pathophysiology

Hruska

Sugatani

Agapova

et al. 2017

Bone

160

140

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The causes of excess cardiovascular mortality associated with chronic kidney disease (CKD) have been attributed in part to the CKD-mineral bone disorder syndrome (CKD-MBD), wherein, novel cardiovascular risk factors have been identified. New advances in the causes of the CKD-MBD are discussed in this review. They demonstrate that repair and disease processes in the kidneys release factors to the circulation that cause the systemic complications of CKD. The discovery of WNT inhibitors, especially Dickkopf 1 (Dkk1), produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. This lead to the discovery that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, wherein it stimulates fibrosis, and decreases tubular klotho expression. Activin A binds to the type 2 activin A receptor, ActRIIA, which is variably affected by CKD in the vasculature. In diabetic/atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC), ActRIIA signaling is inhibited and contributes to CKD induced VSMC dedifferentiation, osteogenic transition and neointimal atherosclerotic calcification. In nondiabetic/nonatherosclerotic aortas, CKD increases VSMC ActRIIA signaling, and vascular fibroblast signaling causing the latter to undergo osteogenic transition and stimulate vascular calcification. In both vascular situations, a ligand trap for ActRIIA prevented vascular calcification. In the skeleton, activin A is responsible for CKD stimulation of osteoclastogenesis and bone remodeling increasing bone turnover. These studies demonstrate that circulating renal repair and injury factors are causal of the CKD-MBD and CKD associated cardiovascular disease.

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Section: Recent Advances In the Pathogenesis Of The Ckd-mbdmentioning

confidence: 99%

The chronic kidney disease — Mineral bone disorder (CKD-MBD): Advances in pathophysiology

Hruska

Sugatani

Agapova

et al. 2017

Bone

160

140

View full text Add to dashboard Cite

show abstract

“…For example, in cross-sectional studies, the presence of renal biomarkers or histopathological changes in the kidney 6 has been associated with the presence of endocrine factors or markers of distant organ dysfunction or damage (such as troponin 7 , B natriuretic peptides 8 or other cardiac biomarkers 9 ). In most clinical studies, crosstalk is used to highlight bivariate associations such as bone-kidney crosstalk 10 , rather than to describe complex multiorgan relationships. The lax use of this term has facilitated the emergence of new syndromic constructs such as cardiorenal syndrome and CKDmineral and bone disorder (CKD-MBD), which has now gained the status of a syndrome 11 .…”

mentioning

confidence: 99%

The systemic nature of CKD

et al. 2017

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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.

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“…The sclerostin expression may represent a counter-regulatory mechanism aimed at suppressing vascular calcification progression. However, more studies are needed to clarify this hypothesis 44. Notably, patients with sclerosteosis or van Buchem’s disease have not been reported to be at increased risk for cardiovascular disease 45.…”

Section: Potential Complications Of Romosozumab Treatmentmentioning

confidence: 99%

Profile of romosozumab and its potential in the management of osteoporosis

Lim

Bolster

2017

DDDT

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Increased understanding of bone biology has led to the discovery of several unique signaling pathways that regulate bone formation and resorption. The Wnt signaling pathway plays a significant role in skeletal development, adult skeletal homeostasis, and bone remodeling. Sclerostin is an inhibitor of the Wnt signaling pathway. Romosozumab, a humanized monoclonal antibody that binds to sclerostin, prevents sclerostin from exerting this inhibitory effect. Therefore, in the presence of romosozumab, the Wnt signaling pathway is activated leading to bone formation and bone mineral density gain. Clinical studies of romosozumab have shown that this agent is one of the most potent bone anabolic agents in development to date. Romosozumab does not act solely as an anabolic agent, but rather, it has effects on increasing bone formation as well as reducing bone resorption. In the clinical studies, patients tolerated romosozumab well with no major safety signals reported. In a Phase III study, romosozumab as compared to placebo has been shown to reduce vertebral fractures by 73% after 1 year of treatment. Sequential therapy with romosozumab for 1 year followed by denosumab in the second year reduced vertebral fractures by 75% as compared to the group that received placebo for 1 year and denosumab in the second year. Romosozumab holds significant potential, by a novel mechanism of action, to expand our ability to treat osteoporosis. More studies are needed to determine the ideal setting in which romosozumab may be used to optimize osteoporosis treatment.

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Sclerostin and DKK1: new players in renal bone and vascular disease

Cited by 130 publications

References 53 publications

The chronic kidney disease — Mineral bone disorder (CKD-MBD): Advances in pathophysiology

The chronic kidney disease — Mineral bone disorder (CKD-MBD): Advances in pathophysiology

The systemic nature of CKD

Profile of romosozumab and its potential in the management of osteoporosis

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