Abstract
The mechanisms of obesity and type 2 diabetes (T2D)-associated impaired fracture healing are poorly studied. In a murine model of T2D reflecting both hyperinsulinemia induced by high-fat diet and insulinopenia induced by treatment with streptozotocin, we examined bone healing in a tibia cortical bone defect. A delayed bone healing was observed during hyperinsulinemia as newly formed bone was reduced by -28.4±7.7% and was associated with accumulation of marrow adipocytes at the defect site +124.06±38.71%, and increased density of SCA1+ (+74.99±29.19%) but not Runx2+ osteoprogenitor cells. We also observed increased in reactive oxygen species production (+101.82±33.05%), senescence gene signature (≈106.66±34.03%), and LAMIN B1- senescent cell density (+225.18±43.15%), suggesting accelerated senescence phenotype. During insulinopenia, a more pronounced delayed bone healing was observed with decreased newly formed bone to -34.9±6.2% which was inversely correlated with glucose levels (R2 = 0.48, P < .004) and callus adipose tissue area (R2 = .3711, P < .01). Finally, to investigate the relevance to human physiology, we observed that sera from obese and T2D subjects had disease state-specific inhibitory effects on osteoblast-related gene signatures in human bone marrow stromal cells which resulted in inhibition of osteoblast and enhanced adipocyte differentiation. Our data demonstrate that T2D exerts negative effects on bone healing through inhibition of osteoblast differentiation of skeletal stem cells and induction of accelerated bone senescence and that the hyperglycemia per se and not just insulin levels is detrimental for bone healing.
Highlights
Delayed union or non-union fracture healing are observed in 5 to 10% of all fractures and result in persistent pain, long-term disability and a need for second surgery, with high personal and socio-economic cost [1].Obesity and type 2 diabetes (T2D) are important factors predisposing to this complication [2,3,4]
We examined dynamics of bone fracture healing of a tibial cortical defect in a murine model of T2D reflecting both hyperinsulinemia caused by insulin resistance induced by high fat diet (HFD) and insulinopenia induced by low doses streptozotocin (STZ) [29]
To study the impact of hyperinsulinemic T2D on bone fracture healing, mice fed with HFD or ND were subjected to a tibial monocortical defect and rate of bone regeneration was determined by μCT scanning at ee day (D)-7, D14 and D21 (Figure 1A)
Summary
Delayed union or non-union fracture healing are observed in 5 to 10% of all fractures and result in persistent pain, long-term disability and a need for second surgery, with high personal and socio-economic cost [1].Obesity and type 2 diabetes (T2D) are important factors predisposing to this complication [2,3,4]. Some studies have demonstrated the presence of a defective bone formation by osteoblastic cells in obese mice [15] and impaired angiogenesis as observed in osteoblast-specific VEGF -deficient mice ee [15,16,17,18]. It is not clear whether hyperglycemia or defective insulin signaling are the underlying mechanisms. Most studies have employed either genetic models e.g. db/db mice that are defective in leptin receptor signaling or obese mice induced by high fat diet (HFD) [19,20] as models of hyperinsulinemia and ev insulin-resistance. The iew relative contribution of hyperinsulinemia versus insulinopenia to defective bone fracture healing, is not known
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