Osteoblast-specific deficiency of ectonucleotide pyrophosphatase or phosphodiesterase-1 engenders insulin resistance in high-fat diet fed mice

Fiona Roberts, Nabil Rashdan, Kanchan Phadwal, Greg Markby, Scott Dillon, Janna Zoll, Julian Berger, Elspeth Milne, Isabel R. Orris, Gerard Karsenty, Olivier Le Saux, Nicholas M Morton, Colin Farquharson, Vicky MacRae

Research output: Contribution to journalArticlepeer-review

Abstract

Supraphysiological levels of the osteoblast-enriched mineralisation regulator ectonucleotide pyrophosphatase/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 KO) exhibited increased femoral bone volume/total volume (17.50% vs 11.67%; p<0.01), and reduced trabecular spacing (0.187mm vs 0.157mm; P<0.01) 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<0.05).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<0.05). 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.
Original languageEnglish
JournalJournal of Cellular Physiology
Early online date10 Dec 2020
DOIs
Publication statusE-pub ahead of print - 10 Dec 2020

Keywords

  • Bone-fat interactions
  • Genetic animal models
  • Matrix mineralization
  • Non collagenous proteinss
  • Osteoblasts

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