TY - JOUR
T1 - Gain-of-Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes
AU - Leanza, Giulia
AU - Fontana, Francesca
AU - Lee, Seung Yon
AU - Remedi, Maria S.
AU - Schott, Céline
AU - Ferron, Mathieu
AU - Hamilton-Hall, Malcolm
AU - Alippe, Yael
AU - Strollo, Rocky
AU - Napoli, Nicola
AU - Civitelli, Roberto
N1 - Funding Information:
This work was supported by a grant from Società Italiana per l'Osteoporosi e le Malattie del Metabolismo Minerale e Scheletrico (SIOMMMS; to Rocky Strollo), from Fondazione Diabete Ricerca‐AMD and Società Italiana di Diabetologia (AMD‐SID; to Giulia Leanza), and by a grant from the Barnes‐Jewish Foundation (to Roberto Civitelli), and National Institutes of Health (NIH) DK098584 (to Maria S. Remedi). Further support was provided by National Institutes of Health (NIH) P30 AR057235 (Core Center for Musculoskeletal Biology and Medicine). We are grateful to Yung Kim and Michael Brodt for their assistance with the bone biomechanics experiments and analysis.
Funding Information:
This work was supported by a grant from Societ? Italiana per l'Osteoporosi e le Malattie del Metabolismo Minerale e Scheletrico (SIOMMMS; to Rocky Strollo), from Fondazione Diabete Ricerca-AMD and Societ? Italiana di Diabetologia (AMD-SID; to Giulia Leanza), and by a grant from the Barnes-Jewish Foundation (to Roberto Civitelli), and National Institutes of Health (NIH) DK098584 (to Maria S. Remedi). Further support was provided by National Institutes of Health (NIH) P30 AR057235 (Core Center for Musculoskeletal Biology and Medicine). We are grateful to Yung Kim and Michael Brodt for their assistance with the bone biomechanics experiments and analysis. Author contributions: Giulia Leanza: Conceptualization; data curation; funding acquisition; investigation; methodology; project administration; writing-original draft. Francesca Fontana: Conceptualization; data curation; formal analysis; investigation; methodology; supervision. Seung-Yon Lee: Data curation; formal analysis; investigation; methodology. Maria Remedi: Data curation; formal analysis; investigation; supervision. Celine Schott: Data curation; investigation. Mathieu Ferron: Data curation; methodology; supervision; writing-review & editing. Malcolm Hamilton-Hall: Data curation; formal analysis; visualization. Yael Alippe: Data curation; investigation; methodology. Rocky Strollo: Conceptualization; funding acquisition; supervision. Nicola Napoli: Conceptualization; data curation; funding acquisition; project administration; supervision; writing-review & editing. Roberto Civitelli: Conceptualization; data curation; formal analysis; funding acquisition; project administration; supervision; writing-original draft; writing-review & editing.
Publisher Copyright:
© 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).
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - BONE
KW - BROWN ADIPOSE TISSUE
KW - DIABETES
KW - Lrp5
KW - WNT SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=85105073328&partnerID=8YFLogxK
U2 - 10.1002/jbmr.4303
DO - 10.1002/jbmr.4303
M3 - Article
C2 - 33831261
AN - SCOPUS:85105073328
SN - 0884-0431
VL - 36
SP - 1403
EP - 1415
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 7
ER -