JOURNAL ARTICLE

Stanniocalcin 2 is associated with ectopic calcification in α-klotho mutant mice and inhibits hyperphosphatemia-induced calcification in aortic vascular smooth muscle cells

Yuichiro Takei, Hironori Yamamoto, Tadatoshi Sato, Ayako Otani, Mina Kozai, Masashi Masuda, Yutaka Taketani, Kazusa Muto-Sato, Beate Lanske, Eiji Takeda
Bone 2012, 50 (4): 998-1005
22285620
Ectopic calcification of soft tissues can have severe clinical consequences especially when localized to vital organs such as heart, arteries and kidneys. Mammalian stanniocalcin (STC) 1 and 2 are glycoprotein hormones identified as calcium/phosphate-regulating hormones. The mRNA of STCs is upregulated in the kidney of α-klotho mutant (kl/kl) mice, which have hypercalcemia, hyperphosphatemia and hypervitaminosis D and exhibit a short life span, osteopenia and ectopic calcification. In the present study, we investigated the distribution and localization of STCs in kl/kl mice. Quantitative RT-PCR revealed that renal mRNA expression of STC2 was increased in both kl/kl mice and fibroblast growth factor 23 (Fgf23)-null mice compared with wild type mice. Interestingly, STC2 protein was focally localized with the calcified lesions of renal arterioles, renal tubular cells, heart and aorta in kl/kl mice. In vitro analysis of rat aortic vascular smooth muscle (A-10) cells showed that inorganic phosphate (Pi) stimulation significantly increased STC2 mRNA levels as well as that of osteocalcin, osteopontin and the type III sodium-dependent phosphate co-transporter (PiT-1), and induced STC2 secretion. Interestingly, the knockdown with a small interfering RNA or the over-expression of STC2 showed acceleration and inhibition of Pi-induced calcification in A-10 cells, respectively. These results suggest that the up-regulation of STC2 gene expression resulting from abnormal α-klotho-Fgf23 signaling may contribute to limitation of ectopic calcification and thus STC2 represents a novel target gene for cardio-renal syndrome.

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