Osteoblast‐specific deficiency of ectonucleotide pyrophosphatase or phosphodiesterase‐1 engenders insulin resistance in high‐fat diet fed mice,Journal of Cellular Physiology

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Osteoblast‐specific deficiency of ectonucleotide pyrophosphatase or phosphodiesterase‐1 engenders insulin resistance in high‐fat diet fed mice
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2020-12-10 , DOI: 10.1002/jcp.30194
Fiona L Roberts ₁ , Nabil A Rashdan ₁ , Kanchan Phadwal ₁ , Greg R Markby ₁ , Scott Dillon ₁ , Janna Zoll ₂ , Julian Berger ₃ , Elspeth Milne ₁ , Isabel R Orriss ₄ , Gerard Karsenty ₃ , Olivier Le Saux ₂ , Nicholas M Morton ₅ , Colin Farquharson ₁ , Vicky E MacRae ₁

Affiliation

Supraphysiological levels of the osteoblast‐enriched mineralization regulator ectonucleotide pyrophosphatase or phosphodiesterase‐1 (NPP1) is associated with type 2 diabetes mellitus. We determined the impact of osteoblast‐specific Enpp1 ablation on skeletal structure and metabolic phenotype in mice. Female, but not male, 6‐week‐old mice lacking osteoblast NPP1 expression (osteoblast‐specific knockout [KO]) exhibited increased femoral bone volume or total volume (17.50% vs. 11.67%; p < .01), and reduced trabecular spacing (0.187 vs. 0.157 mm; p < .01) compared with floxed (control) mice. Furthermore, an enhanced ability of isolated osteoblasts from the osteoblast‐specific KO to calcify their matrix in vitro compared to fl/fl osteoblasts was observed (p < .05). Male osteoblast‐specific KO and fl/fl mice showed comparable glucose and insulin tolerance despite increased levels of insulin–sensitizing under‐carboxylated osteocalcin (195% increase; p < .05). However, following high‐fat‐diet challenge, osteoblast‐specific KO mice showed impaired glucose and insulin tolerance compared with fl/fl mice. These data highlight a crucial local role for osteoblast NPP1 in skeletal development and a secondary metabolic impact that predominantly maintains insulin sensitivity.

中文翻译：

成骨细胞特异性的外核苷酸焦磷酸酶或磷酸二酯酶-1缺乏会导致高脂饮食喂养的小鼠胰岛素抵抗

富含成骨细胞的矿化调节剂焦磷酸酶或磷酸二酯酶-1 (NPP1) 的超生理水平与 2 型糖尿病相关。我们确定了成骨细胞特异性 Enpp1 消融对小鼠骨骼结构和代谢表型的影响。缺乏成骨细胞 NPP1 表达（成骨细胞特异性敲除 [KO]）的雌性而非雄性 6 周龄小鼠表现出股骨骨体积或总体积增加（17.50% vs. 11.67%； p < .01），并且骨小梁减少与 floxed（对照）小鼠相比，间距（0.187 与 0.157 mm； p < .01）。此外，与fl/fl 成骨细胞相比，从成骨细胞特异性 KO 中分离的成骨细胞在体外钙化其基质的能力增强 ( p < .05)。雄性成骨细胞特异性 KO 和fl/fl小鼠表现出相当的葡萄糖和胰岛素耐受性，尽管胰岛素敏感性低羧化骨钙素水平增加（增加 195%； p < .05）。然而，在高脂肪饮食挑战后，与fl/fl小鼠相比，成骨细胞特异性 KO 小鼠的葡萄糖和胰岛素耐受性受损。这些数据强调了成骨细胞 NPP1 在骨骼发育中的关键局部作用以及主要维持胰岛素敏感性的次级代谢影响。

更新日期：2020-12-10

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