Gain-of-Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes
| Autor: | Rocky Strollo, Maria S. Remedi, Seung Yon Lee, Yael Alippe, Malcolm Hamilton-Hall, Nicola Napoli, Francesca Fontana, Céline Schott, Mathieu Ferron, Roberto Civitelli, Giulia Leanza |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty endocrine system Lrp5 endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment 030209 endocrinology & metabolism White adipose tissue 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Bone Density Diabetes mellitus Internal medicine Brown adipose tissue medicine Diabetes Mellitus Animals Humans Insulin Orthopedics and Sports Medicine DIABETES Protein kinase B WNT SIGNALING business.industry Wnt signaling pathway LRP5 Original Articles medicine.disease 030104 developmental biology medicine.anatomical_structure Endocrinology Low Density Lipoprotein Receptor-Related Protein-5 chemistry Gain of Function Mutation Hyperglycemia Mutation Sclerostin BROWN ADIPOSE TISSUE Original Article business BONE hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Bone and Mineral Research |
| ISSN: | 1523-4681 |
| Popis: | High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin, have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin‐deficient diabetes. We introduced the sclerostin‐resistant Lrp5 A214V mutation, associated with high bone mass, in mice carrying the Ins2 Akita mutation (Akita), which results in loss of beta cells, insulin deficiency, and diabetes in males. Akita mice accrue less trabecular bone mass with age relative to wild type (WT). Double heterozygous Lrp5 A214V/Akita mutants have high trabecular bone mass and cortical thickness relative to WT animals, as do Lrp5 A214V single mutants. Likewise, the Lrp5 A214V mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably, Lrp5 A214V/Akita mice develop fasting hyperglycemia and glucose intolerance with a delay relative to Akita mice (7 to 8 vs. 5 to 6 weeks, respectively), despite lack of insulin production in both groups by 6 weeks of age. Although insulin sensitivity is partially preserved in double heterozygous Lrp5 A214V/Akita relative to Akita mutants up to 30 weeks of age, insulin‐dependent phosphorylated protein kinase B (pAKT) activation in vitro is not altered by the Lrp5 A214V mutation. Although white adipose tissue depots are equally reduced in both compound and Akita mice, the Lrp5 A214V mutation prevents brown adipose tissue whitening that occurs in Akita mice. Thus, hyperactivation of Lrp5‐dependent signaling fully protects bone mass and strength in prolonged hyperglycemia and improves peripheral glucose metabolism in an insulin independent manner. Wnt signaling activation represents an ideal therapeutic approach for diabetic patients at high risk of fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). |
| Databáze: | OpenAIRE |
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