scholarly journals Osteoprotegerin Reverses Osteoporosis by Inhibiting Endosteal Osteoclasts and Prevents Vascular Calcification by Blocking a Process Resembling Osteoclastogenesis

2000 ◽  
Vol 192 (4) ◽  
pp. 463-474 ◽  
Author(s):  
Hosung Min ◽  
Sean Morony ◽  
Ildiko Sarosi ◽  
Colin R. Dunstan ◽  
Casey Capparelli ◽  
...  

High systemic levels of osteoprotegerin (OPG) in OPG transgenic mice cause osteopetrosis with normal tooth eruption and bone elongation and inhibit the development and activity of endosteal, but not periosteal, osteoclasts. We demonstrate that both intravenous injection of recombinant OPG protein and transgenic overexpression of OPG in OPG−/2 mice effectively rescue the osteoporotic bone phenotype observed in OPG-deficient mice. However, intravenous injection of recombinant OPG over a 4-wk period could not reverse the arterial calcification observed in OPG−/− mice. In contrast, transgenic OPG delivered from mid-gestation through adulthood does prevent the formation of arterial calcification in OPG−/− mice. Although OPG is normally expressed in arteries, OPG ligand (OPGL) and receptor activator of NF-κB (RANK) are not detected in the arterial walls of wild-type adult mice. Interestingly, OPGL and RANK transcripts are detected in the calcified arteries of OPG−/− mice. Furthermore, RANK transcript expression coincides with the presence of multinuclear osteoclast-like cells. These findings indicate that the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes. Such findings may also explain the observed high clinical incidence of vascular calcification in the osteoporotic patient population.

2021 ◽  
Vol 8 ◽  
Author(s):  
Wenhong Jiang ◽  
Zhanman Zhang ◽  
Yaodong Li ◽  
Chuanzhen Chen ◽  
Han Yang ◽  
...  

Arterial calcification refers to the abnormal deposition of calcium salts in the arterial wall, which results in vessel lumen stenosis and vascular remodeling. Studies increasingly show that arterial calcification is a cell mediated, reversible and active regulated process similar to physiological bone mineralization. The osteoblasts and chondrocytes-like cells are present in large numbers in the calcified lesions, and express osteogenic transcription factor and bone matrix proteins that are known to initiate and promote arterial calcification. In addition, osteoclast-like cells have also been detected in calcified arterial walls wherein they possibly inhibit vascular calcification, similar to the catabolic process of bone mineral resorption. Therefore, tilting the balance between osteoblast-like and osteoclast-like cells to the latter maybe a promising therapeutic strategy against vascular calcification. In this review, we have summarized the current findings on the origin and functions of osteoblast-like and osteoclast-like cells in the development and progression of vascular progression, and explored novel therapeutic possibilities.


2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Cynthia St. Hilaire ◽  
Hui Jin ◽  
Yuting Huang ◽  
Dan Yang ◽  
Alejandra Negro ◽  
...  

Objective: The objective of this study was to develop a patient-specific induced pluripotent stem cell (iPSC)-based disease model to understand the process by which CD73-deficiency leads to vascular calcification in the disease, Arterial Calcification due to Deficiency of CD73 (ACDC). Approach & Results: ACDC is an autosomal recessive disease resulting from mutations in the gene encoding for CD73, which converts extracellular AMP to adenosine. CD73-deficiency manifests with tortuosity and vascular calcification of the medial layer of lower-extremity arteries, a pathology associated with diabetes and chronic kidney disease. We previously identified that dermal fibroblasts isolated from ACDC patients calcify in vitro, however in vivo studies of the vasculature are limited, as murine models of CD73 deficiency do not recapitulate the human disease phenotype. Thus, we created iPSCs from ACDC patients and control fibroblasts. ACDC and Control iPSCs form teratomas when injected in immune-compromised mice, however ACDC iPSC teratomas exhibit extensive calcifications. Control and ACDC iPSCs were differentiated down the mesenchymal lineage (MSC) and while there was no difference in chondrogenesis and adipogenesis, ACDC iMSCs underwent osteogenesis sooner than control iPSC, have higher activity of tissue-nonspecific alkaline phosphatase (TNAP), and lower levels of extracellular adenosine. During osteogenic simulation, TNAP activity in ACDC cells significantly increased adenosine levels, however, not to levels needed for functional compensatory stimulation of the adenosine receptors. Inhibition of TNAP with levimisole ablates this increase in adenosine. Treatment with an A2b adenosine receptor (AR) agonist drastically reduced TNAP activity in vitro, and calcification in ACDC teratomas, as did treatment with etidronate, which is currently being tested in a clinical trial on ACDC patients. Conclusions: These results illustrate a pro-osteogenic phenotype in CD73-deficient cells whereby TNAP activity attempts to compensate for CD73 deficiency, but subsequently induces calcification that can be reversed by activation of the A2bAR. The iPSC teratoma model may be used to screen other potential therapeutics for calcification disorders.


2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Filippo Romanelli ◽  
AnthonyMarco Corbo ◽  
Maryam Salehi ◽  
Manisha C Yadav ◽  
Soha Salman ◽  
...  

Objective: Vascular calcification in asymptomatic individuals is an independent predictor of coronary heart disease (CHD). It is therefore plausible that vascular calcification plays a direct pathophysiological role in atherosclerosis, an underlying cause of CHD. The purpose of this study was to examine the contribution that vascular calcification has on the development of coronary atherosclerosis in a mouse model of familial hypercholesterolemia. Approach and Results: Calcification was induced by overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells of mice harboring a point mutation in the low density lipoprotein receptor ( ldlr, wicked high cholesterol, WHC). Mice were fed an atherogenic diet; echocardiographic and biochemical data were collected longitudinally. Atherosclerosis and vascular calcification were analyzed histologically in the aorta, aortic sinus and coronary arteries. TNAP mice were also treated with a combination of an atherogenic diet and a specific inhibitor of TNAP (SBI-425). Combined with the ldlr mutation and an atherogenic diet, TNAP-driven arterial calcification led to severe atherosclerosis with 100% morbidity characterized by occlusive coronary artery disease, pathological cardiac hypertrophy with dilated LV and reduced ejection fraction (EF). We detected an interaction between vascular calcification and atherosclerosis in mice with endothelial TNAP overexpression. This interaction was particularly prominent in coronary circulation. Targeting TNAP activity therapeutically helped improve survival and heart function of endothelial TNAP overexpressor mice, however the incomplete inhibition of TNAP by SBI-425 was a limitation of this study. Conclusions: Vascular calcification via TNAP overexpression in endothelial cells promotes coronary atherosclerosis and is pathogenic under conditions of hypercholesterolemia.


Nutrients ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 100 ◽  
Author(s):  
Liv M. Vossen ◽  
Abraham A. Kroon ◽  
Leon J. Schurgers ◽  
Peter W. de Leeuw

Vascular calcification is an independent predictor of cardiovascular disease, and therefore, inhibition or regression of this processes is of clinical importance. The standard care regarding prevention and treatment of cardiovascular disease at this moment mainly depends on drug therapy. In animal and preclinical studies, various forms of cardiovascular drug therapy seem to have a positive effect on vascular calcification. In particular, calcium channel blockers and inhibitors of the renin–angiotensin–aldosteron system slowed down arterial calcification in experimental animals. In humans, the results of trials with these drugs are far less pronounced and often contradictory. There is limited evidence that the development of new atherosclerotic lesions may be retarded in patients with coronary artery disease, but existing lesions can hardly be influenced. Although statin therapy has a proven role in the prevention and treatment of cardiovascular morbidity and mortality, it is associated with both regression and acceleration of the vascular calcification process. Recently, nutritional supplements have been recognized as a potential tool to reduce calcification. This is particularly true for vitamin K, which acts as an inhibitor of vascular calcification. In addition to vitamin K, other dietary supplements may also modulate vascular function. In this narrative review, we discuss the current state of knowledge regarding the pharmacological and nutritional possibilities to prevent the development and progression of vascular calcification.


2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Firas Bassissi ◽  
Miguel David Ferrer Reynes ◽  
M Mar Pérez ◽  
Joan Perelló ◽  
Carolina Salcedo

Abstract Background and Aims Peripheral Artery disease (PAD) is a common vascular disease associated with functional impairment and increased risk of cardiovascular events in End Stage Kidney Disease (ESKD) patients undergoing dialysis. Poor limb salvage outcomes and high post-amputation mortality in hemodialysis (HD) patients highlight the need for earlier medical therapies. Cilostazol and pentoxifylline are approved for PAD. Their use in HD patients stays limited and cilostazol use requires caution in this population. Clinical studies demonstrate associations between arterial calcification and adverse outcomes in PAD patients. SNF472, a selective calcification inhibitor that interferes in the formation and growth of hydroxyapatite, is in Phase 3 for calciphylaxis treatment. This study aims to evaluate the effects of SNF472 on limb functional recovery and blood perfusion in a Vitamin D3 (VitD)-induced arterial calcification rat model. Method Arterial calcification was induced in 32 Sprague Dawley rats by 3 consecutive daily s.c. doses of 120 kIU/kg VitD. Rats were divided into four groups and treated during 12 days by: placebo s.c, placebo p.o, SNF472 (20 mg/kg/day, s.c.) or cilostazol (20 mg/kg/day, p.o.). An additional group of 8 rats without VitD received vehicle only (sham). Efficacy was evaluated at day 12 and 17 (5 days after treatment stop). Posterior limb blood perfusion was measured using Laser Doppler Imaging and limb walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a treadmill. Rats were sacrificed at day 26 (14 days after treatment stop), and aortas were collected for calcium analysis. Results VitD-induced arterial calcification was associated with decreased blood perfusion and impairment of limb walking ability (MWT and MWD) compared to sham. SNF472 reduced aorta calcification by 41% compared to placebo. No effects of cilostazol on vascular calcification were observed. The inhibition of calcification in SNF472-treated animals was associated with significant higher limb blood perfusion compared to placebo or Cilostazol (1.28 and 1.37-fold higher, respectively at day 12: p< 0.001) and it was translated into a significant improvement in walking ability compared to placebo (515±114 meters vs 334±187 meters, respectively: p<0.05). Conclusion SNF472 shows improvements in vascular calcification, blood perfusion and a functional parameter like walking distance in a PAD vascular calcification rat model. These results suggest that SNF472 may represent a new therapeutic approach for the treatment of PAD associated with high vascular calcification such as in renal disease.


2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Guillermo Solache-Berrocal ◽  
Valeria Rolle-Sóñora ◽  
Noelia Martín-Fernández ◽  
Serafí Cambray ◽  
José Manuel Valdivielso ◽  
...  

Abstract Background and Aims Individuals with chronic kidney disease (CKD) constitute a population with an exceptionally high cardiovascular risk. Vascular calcification, a common finding in these patients, is a known contributor to cardiovascular disease and several studies suggest it has a certain genetic component. Single nucleotide polymorphisms (SNPs) associated with the extent of calcification in CKD patients could therefore be used to predict individual susceptibility to calcification and subsequent increased cardiovascular risk. We consequently searched for associations of SNPs from candidate genes of known implication in the pathogenesis of vascular calcification (encoding cytokines, extracellular matrix proteins, members of the RANK/RANKL/OPG axis and vitamin D metabolism proteins) with the extent of arterial calcium deposits in order to improve the risk prediction of cardiovascular events in CKD patients. Method The study was performed in 1439 individuals from the NEFRONA population, which include CKD patients (stages 2-3, 4-5, and dialysis) as well as healthy controls recruited from 81 Spanish hospitals. Individuals were genotyped with the iPLEXGOLD MassARRAY technology and Assay Design v4 software for 61 SNPs from 22 genes. A continuous vascular calcification score was calculated from the echogenicity of atherosclerotic plaques detected by ultrasonography in the carotid and femoral arteries. Among several other clinical variables, the presence of cardiovascular events during a 4-year follow up was collected. Association of SNPs with calcification extent was identified by univariate linear regression models. Multiple linear regression with backward elimination was used for the selection of an appropriate SNP-based model adjusted by age, sex and CKD stages. Finally, a Cox proportional hazard regression model was applied for the prediction of cardiovascular risk. Results Arterial calcification scores were higher with increasing age, male sex, and advanced CKD stages (all p<0.001), as expected. Univariate linear regression analyses of all SNPs with the arterial calcification score as dependent variable retrieved p-values <0.05 for 6 six of them (rs11568820, rs2248359, rs2296241, rs3102735, rs385564 and rs495392), which were selected for subsequent analyses. These polymorphisms were next included in a multivariate linear regression model with CKD stage, age and sex as additional independent variables. Only rs2296241 of CYP24A1 (estimate 0.36, 95% CI 0.14 to 0.58, p=0.001 for homocygous GG) and rs495392 of KL (estimate -0.39, 95% CI -0.69 to -0.09, p=0.011 for homocygous TT) remained independently associated with the extent of calcium deposits. Finally, using Cox regression models, it was determined that both the CKD stage (HR [for dialysis stage]=8.34, 95% CI 4.59 to 15.15, p<0.001) and the calcification score (HR=2.05, 95% CI 1.67 to 2.54, p<0.001) predicted the development of cardiovascular events. Considering all possible risk factors, no differences were found in the rate of development of cardiovascular events according to the genotype for the two associated polymorphisms: rs2296241 HR=1.13, 95% CI 0.87 to 1.48, p=0.36; rs495392 HR=0.80 95% CI 0.63 to 1.03, p=0.08. Conclusions Polymorphisms of KL and CYP24A1 genes are associated with the extent of calcification in CKD individuals although they lack the capacity to predict cardiovascular events. However, the echogenic determination of the extent of arterial calcium deposits in CKD patients seems a promising non-invasive, non-irradiating method for the scoring of calcification and even the prediction of cardiovascular events. Further genetic association studies using this technique could therefore yield valuable results.


Author(s):  
Bin Nie ◽  
Shao-qiong Zhou ◽  
Xin Fang ◽  
Shao-ying Zhang ◽  
Si-ming Guan

2013 ◽  
Vol 33 (6) ◽  
pp. 1287-1296 ◽  
Author(s):  
Mariana Kiomy Osako ◽  
Hironori Nakagami ◽  
Munehisa Shimamura ◽  
Hiroshi Koriyama ◽  
Futoshi Nakagami ◽  
...  

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