Converging Mechanisms of Vascular and Cartilaginous Calcification
Abstract
:Simple Summary
Abstract
1. Introduction
2. Types and Characteristics of Ectopic Calcifications: Correspondence with Osteogenesis
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- Intimal calcification is an endochondral ossification process in which type II collagen is mineralized by calcium deposits.
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- Intramembranous ossification is responsible for media calcifications
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- Dystrophic calcification appears in necrotic tissues or as a reaction to tissue destruction leading to valvular calcification.
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- Vascular calciphylaxis or calcific uremic arteriolopathy is a systemic process characterized by diffuse calcification in the media of small and medium arteries or arterioles and intimal proliferation resulting in tissue necrosis.
3. Mechanisms of Vascular and Cartilaginous Calcifications
- (A)
- Induction of osteoblastic–chondrogenic differentiation of VSMCs. In VSMCs of calcified arteries and atherosclerotic plaques, the mineralization process is as follows. VSMCs release MV-like structures, and under conditions of high concentrations of Ca2+ and Pi in the surrounding environment, VSMCs are stimulated to discharge competent MVs for mineralization [25,26]. VSMCs express ALP throughout chondrogenic differentiation, thereby increasing the local Pi level. ALP was also found in MVs released by VSMCs [26,42]. Moreover, in calcified arterial walls, as well as in VSMC culture, HCs had approximately the same pattern of composition during crystal growth as in the case of chondrocytes or bone [44,45]. Figure 3 summarizes the processes of vascular calcification.
- Factors that stimulate chondrogenic transdifferentiation (metaplasia) of VSMCs include mechanical factors (e.g., strain and elongation) [46,47], hypoxia [48,49], Pi (which stimulates the expression of the core binding factor alpha1, a transcription factor associated with osteoblast differentiation and EM mineralization of VSMCs) [50], cytokines, growth factors (e.g., transforming growth factor β (TGF-β), which stimulates the mineralization of VSMCs, and tumor necrosis factor α (TNF-α), which promotes the final differentiation of VSMCs into chondrocyte-like cells) [51,52] and bone morphogenic protein (BMP) 2, which stimulates osteogenic and chondrogenic differentiation [53].
- Factors that promote osteogenic metaplasia include BMP-2 and BMP-4 (while BMP-7 prevents this differentiation) [54], core binding factor alpha 1 [43], Ca2+ and Pi [19], and ALP (which are highly expressed by VSMCs of calcified media vessels) [55]. ALP uses inorganic pyrophosphate (PPi), which is an inhibitor of EM mineralization, as a substrate. Other factors that promote osteogenic transformation are reactive oxygen species (ROS) (i.e., oxidized low-density lipoprotein cholesterol (LDL-C) stimulates the expression of BMP-2 and core binding factor alpha 1] [56]; vitamin D (1,25 dihydroxy vitamin D stimulates ALP activity and exacerbates dystrophic calcifications) [57]; warfarin (a vitamin K antagonist promotes vascular calcification by inhibiting γ-carboxylation of matrix Gla protein (MGP)) [58]; glucocorticoids (e.g., dexamethasone) mediate osteoblast differentiation, thus promoting calcification by suppressing calcification inhibitory molecules) [59]; leptin (a hormone involved in appetite regulation that mediates ectopic calcification by binding and activating β-adrenergic receptors on osteoblasts and increasing the levels of oxidative stress in aortic endothelial cells) [60,61]; and apoptosis (apoptotic remnants of foamy cells, debris VSMCs and MVs increase the local concentration of calcium phosphate, thus promoting an environment suitable for mineral nucleation) [35,43].
- (B)
- Apoptosis. The association between apoptosis and vascular or soft tissue calcification has been widely documented. Vascular calcification is less common because the cellular debris of VSMCs is removed by phagocytic cells, and its clearance may be inhibited under certain conditions, leading to the accumulation of ABs [62,63]. Depending on local conditions, ABs undergo mineralization [64]. Kockx et al. [65] demonstrated that atherosclerotic plaques contain residues of VSMCs and Abs. During apoptosis, Ca2+ and Pi stored in mitochondria and sarcoplasm are incorporated into ABs and contribute to the formation of calcium phosphate crystals. It was found that VSMCs also release vesicles rich in Ca2+ [64]. Anchorage-dependent cells, such as endothelial cells and VSMCs, depend on intercellular and cell–ECM contacts for survival. Integrin has been shown to promote cell survival by inhibiting cell death pathways and activating pro-survival factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The downregulation of vascular endothelial cadherins can induce apoptosis, while the interaction of VSMCs with tenascin C via integrins can prevent apoptosis by changing cell shape and inducing the clustering of epidermal growth factor receptors [66]. Cell–ECM interactions are crucial for apoptotic signaling pathways. Fibronectin signaling through focal adhesion kinase promotes cell survival. Several factors, including mechanical stimulation and growth factors, influence cell survival by activating pathways that prevent apoptosis. Different types of cell death, such as necrosis, apoptosis, and autophagy, affect disease progression in atherosclerosis. Endothelial cell apoptosis is common in the early stage, while VSMC and macrophage apoptosis are common in vulnerable lesions. Factors such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), FGF21 (fibroblast growth factor 21) and antiapoptotic factors regulate apoptosis in vascular cells [67,68]. The regulation of VSMC turnover and apoptosis by miRNAs (e.g., miR-21, miR-26a, and miR-29b) and long noncoding RNAs (lncRNAs) (e.g., taurine upregulated gene 1) that target growth factor pathways and other factors may have therapeutic implications in the treatment of atherosclerosis [69,70]. Understanding the molecular mechanisms of cell survival and death in cardiovascular disease may help develop targeted therapies to prevent vascular death and related pathologies.
- (C)
- The presence of circulating nucleation complexes. Nucleation complexes represent a calcification mechanism that is mostly modulated by the OPG–RANK–RANKL system (osteoprotegerin, a receptor activator of NF-κB, a receptor activator of NF-κB ligand). RANKL is an osteoblastic transmembrane protein that binds to its specific receptor RANK, a member of the TNF superfamily present in preosteoclasts and osteoclasts. The RANKL–RANK system stimulates osteoclastogenesis, whereas OPG (a member of the same TNF superfamily that is synthesized by osteoblasts) opposes this process. Because knockout mice with a deletion of the OPG gene have developed osteoporosis accompanied by severe media calcification of the aorta and renal artery, OPG is considered the main performer in the OPG–RANK–RANKL system [77]. OPG inhibited the arterial calcification induced by warfarin and vitamin D in rats [78]. Thus, we can envisage some of the links between the osteoclastic activity of bone remodeling and vascular calcification. It is acknowledged that RANKL enhances calcification of VSMCs by interacting with RANK and promoting BMP-4 production via activation of the alternative NF-κB pathway. Due to the evidence that RANKL promotes calcification of VSMCs, specific agents such as denosumab, a fully human monoclonal antibody, have been studied for their potential to prevent vascular calcification [79]. Most likely, the major determinant of bone metabolism is the OPG/RANKL ratio. Various factors influence the regulation of the RANKL–RANK–OPG system, such as certain cytokines (TNF-a, IL-1, IL-6 and IL-17), hormones (estrogen, vitamin D, and glucocorticoids), and growth factors [80]. Price et al. [81] suggested that the mineralization of soft tissue was induced by nucleation crystals generated in areas of bone resorption, which circulate through the bloodstream until they attach to tissues where they initiate calcification. In rats, Price et al. [82] discovered a complex consisting of phosphates, Ca2+, fetuin A and MGP (insoluble), which was released into the bloodstream from bone, thus explaining the blood transport of MGP. This complex was not found in humans [83].
- (D)
- Imbalance/decline of inhibitors. An increasing number of ectopic calcification inhibitors are being identified using knockout mice or rat models. The presence of these inhibitors in body fluids and tissues saturated with calcium phosphate ions explains why soft tissues do not calcify instantly. Inhibitors of EM mineralization include OPG; osteopontin (a glycoprotein secreted by osteoblasts and involved in bone remodeling); Ank (a transporting transmembrane protein that controls extracellular PPi export); phosphodiesterase nucleotide pyrophosphatase (an extracellular PPi-generating ectoenzyme) [43]; MGP (involved in the clearance of calcium phosphate but also an inhibitor of osteogenic differentiation of VSMCs in different pathologies) [84,85,86]; fetuin A (a circulating inhibitor of calcification that inhibits de novo formation of HC, but has no effect on the already formed crystals) [87]; and Smad 6 (Smad 6 null mice developed extensive vascular wall calcification and cartilaginous metaplasia in the aorta due to suppression of the BMP signaling pathway) [88].
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Bone Formation | Micro/Macrostructural Characteristics | Mechanism of Mineralization | Localization |
---|---|---|---|
Intramembranous ossification |
|
|
|
Endochondral ossification |
|
|
|
Vascular Calcification | Micro/Macrostructural Characteristics | Mechanism of Mineralization | Associated Pathology |
Intima calcifications |
|
|
|
Media calcifications (Mönckeberg’s sclerosis) |
|
|
|
Calcifications of heart valves |
|
|
|
Vascular calciphylaxis (Calcific uremic arteriolopathy) |
|
|
|
Protective Factors of Calcification | Favoring Factors of Calcification |
---|---|
osteopontin | TNF-α |
OPG | TGF-β |
fetuin-A | oxidized and acetylated LDL-C |
osteonectin | C-reactive protein |
MGP | leptin |
BMP-7 | BMP-2 |
Mg2+ | advanced glycation end-products |
PPi | Pi |
↓ Ca x PO4 | ↑ Ca x PO4 |
vitamin K | interleukin-4 |
HDL-C | interleukin-6 |
growth arrest-specific protein 6 | glucocorticoids |
albumin | ROS |
parathyroid hormone | collagen tip I |
parathyroid hormone related peptide | fibronectin |
phosphonoformic acid | 25-OH colesterol |
natriuretic peptide type C | 17β-estradiol |
adrenomedulin | Ca2+ |
uremic serum | |
1, 25-dihydroxycholecalciferol | |
cyclic adenosine monophosphate |
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Gheorghe, S.R.; Crăciun, A.M.; Ilyés, T.; Tisa, I.B.; Sur, L.; Lupan, I.; Samasca, G.; Silaghi, C.N. Converging Mechanisms of Vascular and Cartilaginous Calcification. Biology 2024, 13, 565. https://doi.org/10.3390/biology13080565
Gheorghe SR, Crăciun AM, Ilyés T, Tisa IB, Sur L, Lupan I, Samasca G, Silaghi CN. Converging Mechanisms of Vascular and Cartilaginous Calcification. Biology. 2024; 13(8):565. https://doi.org/10.3390/biology13080565
Chicago/Turabian StyleGheorghe, Simona R., Alexandra M. Crăciun, Tamás Ilyés, Ioana Badiu Tisa, Lucia Sur, Iulia Lupan, Gabriel Samasca, and Ciprian N. Silaghi. 2024. "Converging Mechanisms of Vascular and Cartilaginous Calcification" Biology 13, no. 8: 565. https://doi.org/10.3390/biology13080565
APA StyleGheorghe, S. R., Crăciun, A. M., Ilyés, T., Tisa, I. B., Sur, L., Lupan, I., Samasca, G., & Silaghi, C. N. (2024). Converging Mechanisms of Vascular and Cartilaginous Calcification. Biology, 13(8), 565. https://doi.org/10.3390/biology13080565