Bone Abstracts

Arterial calcification is now considered as an actively regulated process resembling osteogenesis orchestrated by a number of systemic or constitutively expressed mediators. Genetic studies of rare inherited syndromes have identified key regulators of arterial calcification. Based on the pathogenic principles causing the diseases these can be classified into three groups:

i) Disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio a) Generalized Arterial Calcification of Infancy (GACI) caused by mutations in ENPP1 and ABCC6, b) Pseudoxanthoma Elasticum (PXE) caused by mutations in ABCC6 and ENPP1, c) Arterial Calcification and Distal joint Calcification (ACDC), caused by mutations in NT5E, d) Progeria, caused by mutations in LMNA, e) Idiopathic Basal Ganglia Calcification (IBGC), caused by mutations in SLC20A2, XPR1, PDGFRB and PDGFB, and f) Hyperphosphatemic Familiar Tumoral Calcinosis (HFTC), caused by mutations in KL, GALNT3 and FGF23.

ii) Interferonopathies (Singleton-Merten syndrome), caused by mutations in IFIH1 and DDX58.

iii) Deficiency of Matrix-Gla protein (Keutel syndrome), caused by mutations in MGP. Although some of the identified causative mechanisms are not easy to target, it has become clear that a disturbed extracellular phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on this target to effectively prevent and treat the underlying disease phenotypes.

Disclosure: Receipt of research support from Alexion Pharmaceuticals. Receipt of research support and consultation fees from BioMarin.