Regulation and Function of Rankl in Arterial Calcification

Bartolo, Belinda A. Di; Kavurma, Mary M.

doi:10.2174/1381612820666140212205455

Cited by 5 publications

(3 citation statements)

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“…Mouse OPG knockout studies showed that in the vessel wall the RANKL system is activated in the absence of OPG and this is associated with the presence of multinucleate osteoclast-like cells (88). In vitro studies have further elaborated the roles of OPG showing it can affect a number of cell types and processes including blocking osteoblastic change in VSMCs via direct and paracrine secretion from endothelial cells and this occurs via multiple signaling pathways (89, 90). OPG also appears to play an important role in the context of diabetes by regulating inflammatory responses (91, 92).…”

Section: Osteoprotegerinmentioning

confidence: 99%

Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet

Bäck

Arányi

Cancela

et al. 2019

Front. Cardiovasc. Med.

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The physicochemical deposition of calcium-phosphate in the arterial wall is prevented by calcification inhibitors. Studies in cohorts of patients with rare genetic diseases have shed light on the consequences of loss-of-function mutations for different calcification inhibitors, and genetic targeting of these pathways in mice have generated a clearer picture on the mechanisms involved. For example, generalized arterial calcification of infancy (GACI) is caused by mutations in the enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (eNPP1), preventing the hydrolysis of ATP into pyrophosphate (PPi). The importance of PPi for inhibiting arterial calcification has been reinforced by the protective effects of PPi in various mouse models displaying ectopic calcifications. Besides PPi, Matrix Gla Protein (MGP) has been shown to be another potent calcification inhibitor as Keutel patients carrying a mutation in the encoding gene or Mgp-deficient mice develop spontaneous calcification of the arterial media. Whereas PPi and MGP represent locally produced calcification inhibitors, also systemic factors contribute to protection against arterial calcification. One such example is Fetuin-A, which is mainly produced in the liver and which forms calciprotein particles (CPPs), inhibiting growth of calcium-phosphate crystals in the blood and thereby preventing their soft tissue deposition. Other calcification inhibitors with potential importance for arterial calcification include osteoprotegerin, osteopontin, and klotho. The aim of the present review is to outline the latest insights into how different calcification inhibitors prevent arterial calcification both under physiological conditions and in the case of disturbed calcium-phosphate balance, and to provide a consensus statement on their potential therapeutic role for arterial calcification.

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Section: Osteoprotegerinmentioning

confidence: 99%

Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet

Bäck

Arányi

Cancela

et al. 2019

Front. Cardiovasc. Med.

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“…The RANKL-OPG-RANK axis has been shown to regulate bone remodeling and was more recently found to be involved in carcinogenesis as well as central thermoregulation. This system has also been linked to the development of atherosclerosis and plaque destabilization [127,139]. RANKL exhibits several properties with relevance to atherogenesis, such as promotion of inflammatory responses in T cells and dendritic cells, induction of chemotactic properties in monocytes, induction of MMP activity in vascular smooth muscle cells (SMC), and RANKL has also been found to have prothrombotic properties [74,125,129].…”

Section: Role Opg In Vascular Calcification and Atherosclerosismentioning

confidence: 99%

Vascular Calcification, Atherosclerosis and Bone Loss (Osteoporosis): New Pathophysiological Mechanisms and Future Perspectives for Pharmacological Therapy

2016

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Vascular calcification or ectopic mineralization in blood vessels is an active, cell-regulated process, increasingly recognized as a general cardiovascular risk factor. Ectopic artery mineralization is frequently accompanied by decreased bone mineral density or disturbed bone turnover and development of the osteoporosis. The latest data support the correlation of osteoporosis and atherosclerosis, indicating the parallel progression of two tissue destruction processes with increased fatal and nonfatal coronary events, as well as a higher fracture risk. Patients with osteoporosis, have a higher risk of cardiovascular diseases than subjects with normal bone. Many proteins responsible for bone formation and resorption have been identified in the arterial wall. Vascular calcification includes mostly osteogenic and, to a lesser extent chondrogenic differentiation of osteoblasts and osteoclast-like cells. It has been shown that many of the regulators of bone formation and resorption some bone structural proteins, such as osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) are also expressed in the atherosclerotic plaque. When RANKL binds to RANK, osteoclasts are activated and bone resorption occurs and processes of vascular calcification become also activated. OPG, protein homologue to receptor activator of nuclear factor-κB (RANK), can bind to RANKL, blocking the binding of RANKL to RANK, that results in inhibition of differentiation of preosteoclasts to mature osteoclasts, lower osteoclast capacity for resorption of bone mineral matrix, and development vascular calcification. The latest data supports that cathepsin K, a cysteine protease, can efficiently degrade type I and II collagen, both of which are major matrix components of the bone and atherosclerotic plaque. These findings further underscore the potential of cathepsin K as a target for novel molecules to treat osteoporosis and atherosclerosis. Thus, the discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in the process of bone remodeling, vascular calcification and atherosclerosis has made progress in understanding the mechanisms of disease development and possibly to develop new dual therapies. New therapies for osteoporosis and atherosclerosis that may potentially improve or augment existing treatments include the recently approved anti-receptor activator of NF-κB-ligand monoclonal antibody fms (denosumab) and the cathepsin K inhibitor odanacatib, presently in the late stage of clinical development.

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“…This basic model highlights the protective effect of OPG on VC through the modulation of RANKLs procalcific effects [26].Thus, both RANKL and OPG appear to exert the 'opposite' effects during VC to those typically exerted by either of these ligands during bone remodeling [27], an apparent pathophysiological 'paradox'. A third regulatory protein, TRAIL, has been shown to putatively interact with OPG and RANKL during modulation of the VC process [28], and an emerging hypothesis within the VC field has proposed a vasoprotective role for TRAIL, possibly through pleiotropic effects on vascular gene expression and/or an ability to mediate RANKL signaling. Systemic delivery (both single/repeated injection) of recombinant TRAIL to ApoEnull diabetic mice demonstrated antiatherosclerotic activity [29], and it has been reported that TRAIL has the ability to counteract RANKL's procalcific signals in both cell culture [30] and murine models [31].…”

mentioning

confidence: 99%

The role of OPG/RANKL in the pathogenesis of diabetic cardiovascular disease

Forde

Davenport

Harper

et al. 2018

Cardiovascular Endocrinology &Amp; Metabolism

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Cardiovascular (CV) disease is the leading cause of mortality in patients with type 2 diabetes mellitus. A major factor in the pathogenesis of CV disease is vascular calcification (VC), which is accelerated in type 2 diabetes mellitus. Calcification of the vessel wall contributes to vascular stiffness and left ventricular hypertrophy whereas intimal calcification may predispose to plaque rupture and CV death. The pathogenesis of VC is complex but appears to be regulated by the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) signaling pathway, which is involved in bone remodeling. Within the bone, OPG prevents RANKL from binding to receptor activator of nuclear factor-κB and inhibiting bone resorption. Outside of the bone, the clinical significance of OPG blocking RANKL is not well understood, but OPG knockout mice that lack OPG develop early and severe VC. This minireview outlines some of the research on OPG/RANKL in the pathogenesis of VC and discusses potential therapies, which may reduce VC and CV burden in humans.

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Regulation and Function of Rankl in Arterial Calcification

Cited by 5 publications

References 0 publications

Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet

Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet

Vascular Calcification, Atherosclerosis and Bone Loss (Osteoporosis): New Pathophysiological Mechanisms and Future Perspectives for Pharmacological Therapy

The role of OPG/RANKL in the pathogenesis of diabetic cardiovascular disease

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