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) 2 D, 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) 2 D stimulates sclerostin and inhibits BMP2 production in murine CKD, thus mitigating osteoblastic transdifferentiation and mineralization of soft tissues. Increased osteocytic 1, 25 (OH) 2 D 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.