TY - JOUR
T1 - FOXO1 deletion reverses the effect of diabetic-induced impaired fracture healing
AU - Alharbi, Mohammed A.
AU - Zhang, Citong
AU - Lu, Chanyi
AU - Milovanova, Tatyana N.
AU - Yi, Leah
AU - Ryu, Je Dong
AU - Jiao, Hongli
AU - Dong, Guangyu
AU - Patrick O'Connor, J.
AU - Graves, Dana T.
N1 - Funding Information:
Funding. This work was supported by funding from National Institutes of Health grants R01-AR-060055, R01-DE-017732, and R01-AR-069044. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. M.A.A. designed and carried out experiments, interpreted data, and wrote the manuscript. C.Z. assisted in experimental design, carried out experiments, and interpreted data. C.L. assisted in experimental design and carried out experiments. T.N.M. carried out experiments and edited the manuscript. L.Y. carried out experiments. J.D.R. carried out experiments. H.J. carried out experiments. G.D. carried out experiments. J.P.O. assisted in experimental design and edited the manuscript. D.T.G. designed experiments, interpreted data, and wrote the manuscript. D.T.G. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.2337/db18-0340
DO - 10.2337/db18-0340
M3 - Article
C2 - 30279162
AN - SCOPUS:85056788462
VL - 67
SP - 2682
EP - 2694
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -