title: Stanniocalcin 2 is associated with ectopic calcification in α-klotho mutant mice and inhibits hyperphosphatemia-induced calcification in aortic vascular smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho 3, Tokushima 770-8503, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Takei
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Sato
authors.forename: Ayako
authors.initials: A
authors.lastname: Otani
authors.forename: Mina
authors.initials: M
authors.lastname: Kozai
authors.forename: Masashi
authors.initials: M
authors.lastname: Masuda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Taketani
authors.forename: Kazusa
authors.initials: K
authors.lastname: Muto-Sato
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.forename: Eiji
authors.initials: E
authors.lastname: Takeda
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D002114:Calcinosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054559:Hyperphosphatemia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D010710:Phosphates / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010710:Phosphates; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C485438:Stc2 protein, mouse; D005346:Fibroblast Growth Factors; C051795:teleocalcin; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins