Biomechanics Research Laboratory, Department of Industrial Engineering, University of Miami, Coral Gables, FL, USA.
Biomechanics Research Laboratory, Department of Industrial Engineering, University of Miami, Coral Gables, FL, USA.
J Biomech. 2014 Jul 18;47(10):2269-76. doi: 10.1016/j.jbiomech.2014.04.046. Epub 2014 May 9.
The insulin-like growth factor-1 (IGF-1) is a well-known anabolic agent for intervertebral disc (IVD), promoting both proteoglycan (PG) biosynthesis and cell proliferation. Accordingly, it is believed that IGF-1 may play a central role in IVD homeostasis. Furthermore, the exogenous administration of IGF-1 has been proposed as a possible therapeutic strategy for disc degeneration. The objectives of this study were to develop a new computational framework for describing the mechanisms regulating IGF-mediated homeostasis in IVD, and to apply this numerical tool for investigating the effectiveness of exogenous administration of IGF-1 for curing disc degeneration. A diffusive-reactive model was developed for describing competitive binding of IGF-1 to its binding proteins and cell surface receptors, with the latter reaction initiating the intracellular signaling mechanism leading to PG production and cell proliferation. Because PG production increases cell metabolic rate, and cell proliferation increases nutritional demand, nutrients transport and metabolism were also included into the model, and co-regulated, together with IGF-1, IVD cellularity. The sustainability and the effectiveness of IGF-mediated anabolism were investigated for conditions of pathologically insufficient nutrient supply, and for the case of exogenous administration of IGF-1 to degenerated IVD. Results showed that pathological nutrients deprivation, by decreasing cellularity, caused a reduction of PG biosynthesis. Also, exogenous administration of IGF-1 was only beneficial in well-nourished regions of IVD, and exacerbated cell mortality in malnourished regions. These findings remark the central role of nutrition in IVD health, and suggest that adequate nutritional supply is paramount for achieving a successful IGF-based therapy for disc degeneration.
胰岛素样生长因子-1（IGF-1）是一种众所周知的椎间盘（IVD）合成代谢剂，可促进蛋白聚糖（PG）生物合成和细胞增殖。因此，人们认为 IGF-1 可能在 IVD 稳态中发挥核心作用。此外，外源性给予 IGF-1 已被提议作为治疗椎间盘退变的一种可能的治疗策略。本研究的目的是开发一种新的计算框架，用于描述调节 IGF 介导的 IVD 内稳态的机制，并应用这种数值工具来研究外源性给予 IGF-1 治疗椎间盘退变的效果。开发了一个扩散反应模型来描述 IGF-1 与其结合蛋白和细胞表面受体的竞争结合，后者反应启动了导致 PG 产生和细胞增殖的细胞内信号机制。由于 PG 产生增加了细胞代谢率，并且细胞增殖增加了营养需求，因此还将营养物质运输和代谢纳入模型中，并与 IGF-1 一起共同调节 IVD 的细胞活力。研究了病理性营养供应不足条件下 IGF 介导的合成代谢的可持续性和有效性，以及外源性给予 IGF-1 治疗退变的 IVD 的情况。结果表明，病理性营养剥夺通过降低细胞活力，导致 PG 生物合成减少。此外，外源性给予 IGF-1 仅在 IVD 的营养良好区域有益，而在营养不良区域加剧了细胞死亡率。这些发现强调了营养在 IVD 健康中的核心作用，并表明充足的营养供应对于实现基于 IGF 的椎间盘退变治疗的成功至关重要。
