Anti‐aging Gene Klotho Deficiency Causes Arterial Calcification via Activating the Bone Morphogenetic Protein Signaling

Abstract

BackgroundArterial calcification is an important risk factor for arterial stiffening, hypertension, stroke, and coronary heart disease. Klotho‐deficient mice display severe arterial calcification but the mechanism remains to be determined.Methods & ResultsWe found that Klotho‐deficient mice developed elastin fiber fragmentation and smooth muscle cell (SMC) apoptosis and arterial calcification. Aortas of Klotho (‐/‐) mice demonstrate higher levels of bone morphogenetic proteins (BMP2 and BMP4) and runt‐related transcription factor 2 (RUNX2, a key transcription factor for bone formation). Given that Klotho deficiency‐induced hyperphosphotemia may cause arterial calcification, Klotho deficient mice were given low phosphate diet (0.2%). Interestingly, Low phosphate diet normalized blood phosphate levels and abolished calcification in lungs and kidneys, but it did not prevent the development of aortic calcification in Klotho‐deficient mice. In cultured mouse aortic SMCs, KL‐deficient serum promoted BMP2‐induced calcification, protein expressions of Pit2 (phosphate transporter) and Runx2, and phosphorylation of Smad1/5/8 and Smad2/3. Interestingly, treatment with KL abolished the BMP2‐induced morphogenetic effects.ConclusionKlotho deficiency‐induced arterial calcification is an active process which requires activation of the BMP2 signaling pathway.