Vitamin D–regulated osteocytic sclerostin and BMP2 modulate uremic extraskeletal calcification
Loan Nguyen-Yamamoto, … , Rene St–Arnaud, David Goltzman
Loan Nguyen-Yamamoto, … , Rene St–Arnaud, David Goltzman
Published July 11, 2019
Citation Information: JCI Insight. 2019;4(13):e126467. https://doi.org/10.1172/jci.insight.126467.
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Research Article Bone biology Nephrology

Vitamin D–regulated osteocytic sclerostin and BMP2 modulate uremic extraskeletal calcification

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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Figure 3

Bone sclerostin expression by IHC and serum sclerostin levels.

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Bone sclerostin expression by IHC and serum sclerostin levels. Positive ...
Positive immunohistochemical staining for sclerostin in osteocytes is shown in brown and staining in canaliculi and/or lacunae are shown by the red arrows (A). Counterstaining was with Mayers Hematoxylin. Original magnification, ×400. IHC staining was quantified as the number of positively stained cells per surface area of bone tissue, using ImageJ software, and 300 mm2 (650 × 500 μm) of surface area was analyzed (B). Data are presented as the mean ± SEM of the number of positively stained cells per area of bone tissue (300 mm2) in mice of the indicated genotype. **P ≤ 0.01 compared with mice of the same genotype maintained on a non-adenine–containing diet determined by Student’s t test, ◊◊P ≤ 0.01 compared to WT mice on a non-adenine diet determined by ANOVA with Bonferroni adjustment. Serum levels of sclerostin in WT mice, osteocyte-specific 1αOHase–/– KO mice (Oct), and global 1αOHase–/– KO mice (Global). (C). Numbers refer to weeks after beginning adenine and data are expressed as the mean ± SEM (n = 6–8 mice of each genotype). **P ≤ 0.01, *P ≤ 0.05 compared with mice of the same genotype maintained on a non-adenine–containing diet determined by ANOVA with Bonferroni adjustment.