Gain-of-Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of
Giulia Leanza1,2, Francesca Fontana1, Seung-Yon Lee1
1Division of Bone and Mineral Diseases, Department of Medicine, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
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 Lrp5A214V mutation, associated with high bone mass, in mice carrying the Ins2Akita 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 Lrp5A214V /Akita mutants have high trabecular bone mass and cortical thickness relative to WT animals, as do Lrp5A214V single mutants. Likewise, the Lrp5A214V mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably, Lrp5A214V /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 Lrp5A214V /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 Lrp5A214V mutation. Although white adipose tissue depots are equally reduced in both compound and Akita mice, the Lrp5A214V 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).
Insights
Activating Wnt signaling via Lrp5 mutation fully protects bone mass and strength in diabetic mice. This approach also improves glucose metabolism independently of insulin, offering a potential therapeutic strategy for diabetic fracture risk.
Area of Science:
- Endocrinology
- Bone Biology
- Metabolic Diseases
Background:
- Diabetic patients exhibit high fracture rates and elevated sclerostin, a Wnt inhibitor.
- Insulin-deficient diabetes mouse models show reduced bone mass with age.
Purpose of the Study:
- To investigate the effects of Wnt signaling activation on bone health in a mouse model of insulin-deficient diabetes.
- To determine if Lrp5 mutation can mitigate bone loss and metabolic dysfunction in diabetes.
Main Methods:
- Introduced a sclerostin-resistant Lrp5A214V mutation into Ins2Akita diabetic mice.
- Assessed bone mass, cortical thickness, biomechanical properties, glucose metabolism, and adipose tissue characteristics.
Main Results:
- Lrp5A214V mutation preserved trabecular bone mass and cortical thickness in diabetic mice.
- The mutation prevented deterioration of bone biomechanical properties.
- Lrp5A214V /Akita mice showed delayed hyperglycemia and improved glucose metabolism independently of insulin.
- Prevented brown adipose tissue whitening in diabetic mice.
Conclusions:
- Hyperactivation of Lrp5-dependent Wnt signaling fully protects bone mass and strength during prolonged hyperglycemia.
- Wnt signaling activation improves peripheral glucose metabolism independent of insulin.
- Wnt signaling activation is a promising therapeutic strategy for diabetic patients at high risk of fracture.
