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

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• 作者：Yuichiro Takei^a ; ¹ ; ² ; Hironori Yamamoto^a ; ¹ ; ^{yamamoto@nutr.med.tokushima-u.ac.jp} ; Tadatoshi Sato^b ; Ayako Otani^a ; Mina Kozai^a ; Masashi Masuda^a ; ³ ; Yutaka Taketani^a ; Kazusa Muto-Sato^a ; ⁴ ; Beate Lanske^b ; Eiji Takeda^a
• 关键词：Stanniocalcin 2 (STC2) ; ¦Á-Klotho mutant mice (kl/kl) ; Fgf-23 ; Ectopic calcification ; Hyperphosphatemia
• 刊名：Bone
• 出版年：2012
• 出版时间：April, 2012
• 年：2012
• 卷：50
• 期：4
• 页码：998-1005
• 全文大小：1564 K

文摘

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 ¦Á-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 ¦Á-klotho-Fgf23 signaling may contribute to limitation of ectopic calcification and thus STC2 represents a novel target gene for cardio-renal syndrome.