Ectopic mineralization disorders of the extracellular matrix of connective tissue: molecular genetics and pathomechanisms of aberrant calcification

Abstract

Ectopic mineralization of connective tissues is a complex process leading to deposition of calcium phosphate complexes in the extracellular matrix, particularly affecting the skin and the arterial blood vessels and common in age-associated disorders. A number of initiating and contributing metabolic and environmental factors are linked to aberrant mineralization in these diseases, making the identification of precise pathomechanistic pathways exceedingly difficult. However, there has been significant recent progress in understanding the ectopic mineralization processes through study of heritable single-gene disorders, which have allowed identification of discrete pathways and contributing factors leading to aberrant connective tissue mineralization. These studies have provided support for the concept of an intricate mineralization/anti-mineralization network present in peripheral connective tissues, providing a perspective to development of pharmacologic approaches to limit the phenotypic consequences of ectopic mineralization. This overview summarizes the current knowledge of ectopic heritable mineralization disorders, with accompanying animal models, focusing on pseudoxanthoma elasticum and generalized arterial calcification of infancy, two autosomal recessive diseases manifesting with extensive connective tissue mineralization in the skin and the cardiovascular system.

Keywords: Ectopic mineralization; Generalized arterial calcification of infancy; Heritable connective tissue diseases; Pathomechanisms of mineralization disorders; Pseudoxanthoma elasticum.

Figure 1. Clinical and histopathologic features of pseudoxanthoma elasticum (A–C) and generalized arterial calcification of infancy (D–E)

(A) Characteristic skin lesions consisting of yellowish papules coalescing into an inelastic plaque of skin on the side of the neck (arrow). (B) Fundoscopic examination reveals angioid streaks (arrow). (C) Histopathology of skin demonstrates accumulation of pleiomorphic elastic structures which are mineralized in the middermis (arrows; von Kossa stain). (D) Computed tomography angiogram of the heart reveals abnormal calcification of the left circumflex artery (white arrow) and left main coronary artery (black arrow) in a 2 year-old patient. (E) Prenatal ultrasound demonstrates extensive calcification of the aortic bifurcation (arrows). (F) Calcification of mesenteric artery in a newborn (arrow; von Kossa stain).

Figure 2. Genetic complexity of the mineralization/anti-mineralization network in connective tissues

Mutations in specific genes can contribute to deposition of hydroxyapatite in heritable ectopic mineralization disorders: NFTC, normophosphatemic familial tumoral calcinosis; HFTC, hyperphosphatemic FTC; PXE, pseudoxanthoma elasticum; GACI, generalized arterial calcification of infancy; ACDC, arterial calcification due to CD73 deficiency. The blue solid circles represent currently unidentified anti-mineralization factors physiologically transported by ABCC6 from intracellular milieu (IC) to the extracellular space (EC). (Adapted from Li and Uitto, 2013, with permission).