FOXO1 deletion reverses the effect of diabetic-induced impaired fracture healing

Mohammed A. Alharbi, Citong Zhang, Chanyi Lu, Tatyana N. Milovanova, Leah Yi, Je Dong Ryu, Hongli Jiao, Guangyu Dong, J. Patrick O'Connor, Dana T. Graves

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Abstract

Type 1 diabetes impairs fracture healing. We tested the hypothesis that diabetes affects chondrocytes to impair fracture healing through a mechanism that involves the transcription factor FOXO1. Type 1 diabetes was induced by streptozotocin in mice with FOXO1 deletion in chondrocytes (Col2α1Cre+.FOXO1L/L) or littermate controls (Col2α1Cre2.FOXO1L/L) and closed femoral fractures induced. Diabetic mice had 77% less cartilage and 30% less bone than normoglycemics evaluated histologically and by micro-computed tomography. Both were reversed with lineage-specific FOXO1 ablation. Diabetic mice had a threefold increase in osteoclasts and a two-to threefold increase in RANKL mRNA or RANKL-expressing chondrocytes compared with normoglycemics. Both parameters were rescued by FOXO1 ablation in chondrocytes. Conditions present in diabetes, high glucose (HG), and increased advanced glycation end products (AGEs) stimulated FOXO1 association with the RANKL promoter in vitro, and overexpression of FOXO1 increased RANKL promoter activity in luciferase reporter assays. HG and AGE stimulated FOXO1 nuclear localization, which was reversed by insulin and inhibitors of TLR4, histone deacetylase, nitric oxide, and reactive oxygen species. The results indicate that chondrocytes play a prominent role in diabetes-impaired fracture healing and that high levels of glucose, AGEs, and tumor necrosis factor-α, which are elevated by diabetes, alter RANKL expression in chondrocytes via FOXO1.

Original languageEnglish (US)
Pages (from-to)2682-2694
Number of pages13
JournalDiabetes
Volume67
Issue number12
DOIs
StatePublished - Dec 1 2018

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All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Alharbi, M. A., Zhang, C., Lu, C., Milovanova, T. N., Yi, L., Ryu, J. D., Jiao, H., Dong, G., Patrick O'Connor, J., & Graves, D. T. (2018). FOXO1 deletion reverses the effect of diabetic-induced impaired fracture healing. Diabetes, 67(12), 2682-2694. https://doi.org/10.2337/db18-0340