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
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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