Multiple Pathways for Pathological Calcification in the Human Body

Abstract

Biomineralization of skeletal components (e.g., bone and teeth) is generally accepted to occur under strict cellular regulation, leading to mineral–organic composites with hierarchical structures and properties optimized for their designated function. Such cellular regulation includes promoting mineralization at desired sites as well as inhibiting mineralization in soft tissues and other undesirable locations. In contrast, pathological mineralization, with potentially harmful health effects, can occur as a result of tissue or metabolic abnormalities, disease, or implantation of certain biomaterials. This progress report defines mineralization pathway components and identifies the commonalities (and differences) between physiological (e.g., bone remodeling) and pathological calcification formation pathways, based, in part, upon the extent of cellular control within the system. These concepts are discussed in representative examples of calcium phosphate‐based pathological mineralization in cancer (breast, thyroid, ovarian, and meningioma) and in cardiovascular disease. In‐depth mechanistic understanding of pathological mineralization requires utilizing state‐of‐the‐art materials science imaging and characterization techniques, focusing not only on the final deposits, but also on the earlier stages of crystal nucleation, growth, and aggregation. Such mechanistic understanding will further enable the use of pathological calcifications in diagnosis and prognosis, as well as possibly provide insights into preventative treatments for detrimental mineralization in disease.

FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes

“…Arterial calcification is also described in OPN deficiency or hypophosphorylation [ 116 ]. However, tumor microcalcifications in the form of hydroxyapatite have also been associated with high OPN expression, without a known mechanism [ 117 , 118 ]. These contradictory actions stress the need to study sortilin 1 and OPN phosphorylation states in soft tissues, including the brain, which has high expression of OPN and sortilin 1, to elucidate the ectopic calcifications observed in RS.…”

Engineered In vitro Models for Pathological Calcification: Routes Toward Mechanistic Understanding

“…[ 75 ] Breast MCs are calcium mineral deposits in breast tissue that are an important screening tool for diagnosis of benign or malignant breast cancer. [ 76 ] Studies showed the morpgology of MC can be related to the aggressiveness of the tumor, for example, casting‐type MCs are reported in aggressive tumor pathology compared to crushed stone (pleomorphic) or powdery. [ 75,76 ] The overexpression of human epidermal growth factor receptor type 2 (HER‐2) is highly associated with the occurrence of MCs in premalignant breast lesions, which can be an indicator of aggressive tumor growth.…”

“…[ 76 ] Studies showed the morpgology of MC can be related to the aggressiveness of the tumor, for example, casting‐type MCs are reported in aggressive tumor pathology compared to crushed stone (pleomorphic) or powdery. [ 75,76 ] The overexpression of human epidermal growth factor receptor type 2 (HER‐2) is highly associated with the occurrence of MCs in premalignant breast lesions, which can be an indicator of aggressive tumor growth. [ 75,77 ] The relationship of MCs and breast cancer prognosis is not clear yet.…”

“…To understand the connection of malignancy of breast cancer and MCs mineral characteristics, in vitro models have been applied. [ 76 ] Moreover, tissue‐engineered scaffolds are used as in vitro platform to study the effect of HAp particle size on mammary cancer cell activity. [ 152 ] The mineral‐containing poly(lactide‐co‐glycolide) (PLG) scaffold showed that the particle size of HAp crystals modulates protein adsorption.…”

Crystal size in μcrystalline pathologies and its clinical implication

“…Microcrystalline pathology is an exciting research field [1][2][3][4][5][6][7][8][9][10] in which most investigations have been performed on the mineral component of the biological deposits induced by the pathology. With respect to urolithiasis, the morphoconstitutional model defines the morphology of the kidney stones as one of the key parameters to establish a link between the At the mesoscopic scale, the morphology and size of crystallites can be determined by scanning electron microscopy (SEM) [6,20,21], while at the nanometric scale, the size of crystals is determined by X-ray scattering [22][23][24], powder neutron diffraction (PND) [25,26], X-ray absorption spectroscopy [27][28][29][30][31] or by transmission electron microscopy [32][33][34][35][36].…”