elastin and Bone-Diseases--Metabolic

Disturbances in bone and mineral metabolism in patients with chronic kidney disease (CKD) affect not only the bone diseases but also other organ disorders in the whole body and deteriorate the survival of these patients. The term CKD-Mineral and Bone Disorder (CKD-MBD) has been established describing a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD. Vascular calcification and secondary hyperparathyroidism are major diseases in CKD-MBD.

Topics: Apoptosis; Bone Density; Bone Diseases, Metabolic; Calcinosis; Chronic Disease; Elastin; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Muscle, Smooth, Vascular; Receptors, Calcitriol; Receptors, Calcium-Sensing; Vascular Diseases

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1

Topics: Animals; Bone Diseases, Metabolic; Collagen; Cutis Laxa; Elastin; Extracellular Matrix Proteins; Humans; Mice