Bioinformatic analysis of factors involved in age-related mineralization of soft tissues - Anastasia Shindyapina

Video Overview

Age-related metastatic mineralization of the soft tissues was historically considered to be a passive and spontaneous process. Recent data demonstrate that calcium salts deposition in soft tissues could be a highly regulated process. Mechanisms leading to this pathology vary in different patients and depend on disease type, stage, patient gender, and age.

Although calcification occurs in any tissue type, vascular calcification has been of particular interest due to association with atherosclerosis, chronic kidney disease (CKD), and osteoporosis. Patients with these age-related disorders explore different mechanisms underlying calcium apatite accumulation. In case of atherosclerotic plaque oxy-lipids triggers release of the pro-inflammatory cytokines and inflammation that activate calcification processes in intimae aorta. Recent in vitro study demonstrates that oxy-lipids can accelerate vascular smooth muscle cells (VSMC) calcification in a dose-dependent manner. In CKD patients renal failure alter the balance between calcium and phosphate levels that usually regulated by FGF23, Klotho, and vitamin D. With accumulation of both phosphate and calcium ions VSMC begin to explore osleoblast-like phenotype. Finally, bone-derived matrix vesicles in osteoporotic patients can degrade extracellular matrix of tissues and accelerate calcium apatite growth.

There are many processes leading to calcification of structural cells and extracellular matrix. Collagen is a major component of extracellular matrix and modifications of collagen fibers accumulate with age. Formation of cross-links between collagen fibers are regulated by action of the lysine hydroxylases and lysyl oxidase, and could occur spontaneously. Oxidation-induced AGEs is a major type of spontaneous cross-links that accelerate with age and may result in tissue stiffness, problems with recycling and potentially accumulation of calcium apatite. The accumulation of AGEs and the rate of mineralization may be interrelated. Applying strategies for clearing the AGEs proposed by de Grey, may be more difficult in the highy-mineralized extracellular matrix.

We performed bioinformatic analysis of the molecular pathways underlying calcification in atherosclerotic and CKD patients, signaling pathways of collagen cross-links formation and bone mineralization and proposed new potential targets for calcification treatment and review drugs for the targets.