Modeling the role of ATP metabolism in articular cartilage and osteoarthritis

IF 1.9 4区 生物学 Q2 BIOLOGY
Dhruba Jyoti Mech, Mohd Suhail Rizvi
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引用次数: 0

Abstract

Osteoarthritis, a prevalent degenerative joint disease, is characterized by progressive degradation of articular cartilage. The avascular nature of articular cartilage makes it vulnerable to metabolic disruptions under hypoxic conditions. Central to this process is the role of ATP metabolism in chondrocytes, which generally maintains a delicate balance between glycolysis and oxidative phosphorylation. To investigate the balance between these two mechanisms and their regulation, we developed a comprehensive mathematical model simulating ATP metabolism in chondrocytes. The model incorporates key metabolic regulators, capturing the bistable switching between glycolysis and oxidative phosphorylation under varying nutrient conditions. Our simulation also accounts for stochastic fluctuations in oxygen and glucose levels, mimicking physiological conditions during mechanical loading, and their impact on articular cartilage dynamics. The results demonstrate that chronic hypoxia induces an irreversible metabolic shift to glycolysis, leading to sustained reductions in ATP levels and progressive ECM loss. Interestingly, the model predicts that physiological stochasticity in oxygen levels, representative of mechanical loading during physical activity, enhances metabolic flexibility and promotes ATP synthesis. When testing therapeutic interventions, we found that while exogenous ECM supplementation provides transient matrix restoration, only approaches targeting metabolic dysfunction — either through enhanced ATP synthesis or controlled suppression of regulatory factors — successfully reverse the pathological glycolytic shift. Our model suggests that optimal therapeutic approaches should combine ATP metabolic modulation with structural support to maintain beneficial nutrient fluctuations. The framework provides a basis for the development of personalized treatment strategies that address both the metabolic and structural aspects of osteoarthritis, offering new possibilities for restoring cartilage homeostasis and preventing disease progression.
模拟ATP代谢在关节软骨和骨关节炎中的作用
骨关节炎是一种常见的退行性关节疾病,其特征是关节软骨的进行性退化。关节软骨的无血管性质使其在缺氧条件下易受代谢破坏。这个过程的核心是软骨细胞中ATP代谢的作用,它通常维持糖酵解和氧化磷酸化之间的微妙平衡。为了研究这两种机制之间的平衡及其调控,我们建立了一个模拟软骨细胞ATP代谢的综合数学模型。该模型结合了关键的代谢调节因子,在不同的营养条件下捕获糖酵解和氧化磷酸化之间的双稳态切换。我们的模拟还考虑了氧和葡萄糖水平的随机波动,模拟了机械负荷期间的生理条件,以及它们对关节软骨动力学的影响。结果表明,慢性缺氧诱导不可逆的代谢转变为糖酵解,导致ATP水平持续降低和进行性ECM损失。有趣的是,该模型预测了氧水平的生理随机性,代表了身体活动期间的机械负荷,增强了代谢灵活性并促进了ATP的合成。在测试治疗干预措施时,我们发现,虽然外源性ECM补充提供了短暂的基质恢复,但只有针对代谢功能障碍的方法——要么通过增强ATP合成,要么通过控制调节因子的抑制——才能成功逆转病理性糖酵解转变。我们的模型表明,最佳的治疗方法应该结合ATP代谢调节和结构支持,以维持有益的营养波动。该框架为骨关节炎的代谢和结构方面的个性化治疗策略的发展提供了基础,为恢复软骨稳态和预防疾病进展提供了新的可能性。
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来源期刊
Biosystems
Biosystems 生物-生物学
CiteScore
3.70
自引率
18.80%
发文量
129
审稿时长
34 days
期刊介绍: BioSystems encourages experimental, computational, and theoretical articles that link biology, evolutionary thinking, and the information processing sciences. The link areas form a circle that encompasses the fundamental nature of biological information processing, computational modeling of complex biological systems, evolutionary models of computation, the application of biological principles to the design of novel computing systems, and the use of biomolecular materials to synthesize artificial systems that capture essential principles of natural biological information processing.
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