Abstract:
Bone has the fascinating ability to self-regenerate. However, under certain conditions, such as type 2 diabetes mellitus (T2DM), this ability is impaired. T2DM is a chronic metabolic disease known by the presence of elevated blood glucose levels that is associated with reduced bone regeneration capability, high fracture risk, and eventual non-union risk after a fracture. Several mechanical and biological factors relevant to bone regeneration have been shown to be affected in a diabetic environment. However, whether impaired bone regeneration in T2DM can be explained due to mechanical or biological alterations remains unknown. To elucidate the relevance of either one, the aim of this study was to investigate the relative contribution of T2DM-related alterations on either cellular activity or mechanical stimuli driving bone regeneration. A previously validated in silico computer modeling approach that was capable of explaining bone regeneration in uneventful conditions of healing was further developed to investigate bone regeneration in T2DM. Aspects analyzed included the presence of mesenchymal stromal cells (MSCs), cellular migration, proliferation, differentiation, apoptosis, and cellular mechanosensitivity. To further verify the computer model findings against in vivo data, an experimental setup was replicated, in which regeneration was compared in healthy and diabetic after a rat femur bone osteotomy stabilized with plate fixation. We found that mechanical alterations had little effect on the reduced bone regeneration in T2DM and that alterations in MSC proliferation, MSC migration, and osteoblast differentiation had the highest effect. In silico predictions of regenerated bone in T2DM matched qualitatively and quantitatively those from ex vivo μCT at 12 weeks post-surgery when reduced cellular activities reported in previous in vitro and in vivo studies were included in the model. The presented findings here could have clinical implications in the treatment of bone fractures in patients with T2DM. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
摘要:
骨骼具有迷人的自我再生能力。然而,在一定条件下,例如2型糖尿病(T2DM),这种能力受损。T2DM是一种慢性代谢性疾病,已知血糖水平升高与骨再生能力降低有关。高骨折风险,和骨折后最终不愈合的风险。与骨再生相关的几种机械和生物因素已被证明在糖尿病环境中受影响。然而,2型糖尿病患者骨再生受损是否可以由机械或生物学改变引起,目前尚不清楚.为了阐明两者的相关性,本研究的目的是研究T2DM相关改变对细胞活性或机械刺激驱动骨再生的相对贡献.进一步开发了一种先前经过验证的计算机模拟方法,该方法能够解释在正常愈合条件下的骨再生,以研究T2DM的骨再生。分析的方面包括间充质基质细胞(MSC)的存在,细胞迁移,扩散,分化,凋亡,和细胞机械敏感性。为了进一步验证计算机模型对体内数据的发现,复制了一个实验装置,其中比较了健康和糖尿病患者在用钢板固定稳定的大鼠股骨截骨术后的再生。我们发现机械改变对T2DM的骨再生减少几乎没有影响,而MSC增殖改变,MSC迁移,成骨细胞分化效果最高。当先前的体外和体内研究中报道的细胞活性降低时,在手术后12周时,T2DM中再生骨的计算机预测在定性和定量上与来自离体μCT的那些相匹配。本文提出的发现可能对T2DM患者的骨折治疗具有临床意义。©2023作者。JBMRPlus由WileyPeriodicalsLLC代表美国骨骼和矿物研究学会出版。