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Abstract
We induced chronic kidney disease (CKD) with adenine in WT mice, mice with osteocyte-specific deletion of Cyp27b1, encoding the 25-hydroxyvitamin D 1(OH)ase [Oct-1(OH)ase–/–], and mice with global deletion of Cyp27b1 [global-1α(OH)ase–/–]; we then compared extraskeletal calcification. After adenine treatment, mice displayed increased blood urea nitrogen, decreased serum 1,25(OH)2D, and severe hyperparathyroidism. Skeletal expression of Cyp27b1 and of sclerostin and serum sclerostin all increased in WT mice but not in Oct-1α(OH)ase–/– mice or global-1α(OH)ase–/– mice. In contrast, skeletal expression of BMP2 and serum BMP2 rose in the Oct-1α(OH)ase–/– mice and in the global-1α(OH)ase–/– mice. Extraskeletal calcification occurred in muscle and blood vessels of mice with CKD and was highest in Oct-1α(OH)ase–/–mice. In vitro, recombinant sclerostin (100 ng/mL) significantly suppressed BMP2-induced osteoblastic transdifferentiation of vascular smooth muscle A7r5 cells and diminished BMP2-induced mineralization. Our study provides evidence that local osteocytic production of 1,25(OH)2D stimulates sclerostin and inhibits BMP2 production in murine CKD, thus mitigating osteoblastic transdifferentiation and mineralization of soft tissues. Increased osteocytic 1,25(OH)2D production, triggered by renal malfunction, may represent a “primary defensive response” to protect the organism from ectopic calcification by increasing sclerostin and suppressing BMP2 production.
Authors
Loan Nguyen-Yamamoto, Ken-Ichiro Tanaka, Rene St–Arnaud, David Goltzman
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