Experimental and Molecular Pathology

2009

DOI: 10.1016/j.yexmp.2008.11.001

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Atherosclerotic inflammation triggers osteogenic bone transformation in calcified and stenotic human aortic valves: Still a matter of debate

Thomas Anger¹,

Walter Carson²,

Michael Weyand³

et al.

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Role Of Lipoproteins and Inflammation Process1

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Cited by 18 publications

(15 citation statements)

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“…A similar mechanism was suggested for valvular calcification [78]. In contrast, a DNA microarray analysis of human calcified aortic valves detected elevated inflammatory markers but no upregulation of osteoblastic markers [79]. In addition, it was shown that the deposition of calcium-phosphate was passive and the osteogenic differentiation of VSMCs happened after the initial calcification [58,80].…”

Section: Discussionmentioning

confidence: 69%

Lumenal calcification and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity

¹

,

²

,

³

et al. 2020

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The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP)-rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization (calcification). The mutant mouse strain D2,Ahsg-/-combines fetuin-A deficiency with the calcification-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue calcification. Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. We analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/-mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genomewide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis. Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.

“…A similar mechanism was suggested for valvular calcification [78]. In contrast, a DNA microarray analysis of human calcified aortic valves detected elevated inflammatory markers but no upregulation of osteoblastic markers [79]. In addition, it was shown that the deposition of calcium-phosphate was passive and the osteogenic differentiation of VSMCs happened after the initial calcification [58,80].…”

Section: Discussionmentioning

confidence: 69%

Lumenal calcification and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity

¹

,

²

,

³

et al. 2020

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The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP)-rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization (calcification). The mutant mouse strain D2,Ahsg-/-combines fetuin-A deficiency with the calcification-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue calcification. Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. We analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/-mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genomewide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis. Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.

“…A similar mechanism was suggested for valvular calcification [73]. In contrast, a DNA microarray analysis of human calcified aortic valves detected elevated inflammatory markers but no upregulation of osteoblastic markers [74]. In addition, it was shown that the deposition of calcium-phosphate was passive and the osteogenic differentiation of VSMCs happened after the initial calcification [56,75].…”

Section: Discussionmentioning

confidence: 69%

Microvasculopathy, Luminal Calcification and Premature Aging in Fetuin-A Deficient Mice

¹

,

²

,

³

et al. 2019

Preprint

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Objective -The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP) -rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore ectopic mineralization (calcification). The mutant mouse strain D2,Ahsg-/-combines fetuin-A deficiency with the mineralization-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue mineralization. Here we studied mechanisms leading to soft tissue mineralization, organ damage and premature aging in these mice.Approach and Results -We analyzed mice longitudinally by echocardiography, X-raycomputed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/-mice.Fetuin-A deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature aging. Importantly, early stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the ectopic mineralization was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis.Conclusions -Collectively, these results demonstrate that pathological mineralization can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of mineralized matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.

“…Tenascin C, which has been involved in growth promotion, stimulation of bone formation, and mineralization, is present in calcified aortic leaflets and is both co-expressed and overexpressed with matrix metalloproteinases [7][8][9][10][11][12][13]. Tenascin C, which has been involved in growth promotion, stimulation of bone formation, and mineralization, is present in calcified aortic leaflets and is both co-expressed and overexpressed with matrix metalloproteinases [7][8][9][10][11][12][13].…”

Section: Role Of Lipoproteins and Inflammation Processmentioning

confidence: 99%

Pharmacotherapy of Aortic Stenosis-Success or Failure?

2012

Current Pharmaceutical Biotechnology

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Aortic stenosis (AS) is a degenerative valvular disease that has, until recently, been considered to be a progressive and the most importantly unmodifiable process. However, recent histopathologic studies have clearly reported that the both development and progression of AS is based on an biochemically active process which is mediated by a chronic inflammation (featured by many similarities with atherosclerosis) and includes inflammatory-cell infiltrates, lipoproteins, lipids and factors responsible for calcification (extracellular-bone-matrix proteins and bone mineral). Targeted drug therapy to prevent the progression of calcific AS disease should ideally be based on the knowledge of risk factors and the molecular pathogenesis of the disease. Treatment trials using various drugs have been undertaken to test whether medical therapy (statins, renin-angiotensin inhibition and anti-osteoporosis drugs) can prevent or beneficially modify the disease course. Although retrospective and non-randomized studies suggested a positive effect of statins, benefit has not been seen in perspective randomized controlled trials. Inhibition of renin-angiotensin has shown discordant results in retrospective studies with no randomized controlled data published. In the future, we need to consider other medical therapies (antiosteoporosis drugs are attractive candidates) that might target different pathways in this disease process. Additionally, we need to detect the optimal moment to start statin therapy for this chronic slowly progressive disease; treatments aimed at the early disease process (pre-obstructive form of aortic sclerosis) may be ineffective with end-stage tissue changes.

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