Rescuing Loading Induced Bone Formation at Senescence

The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.

全球骨质疏松症（osteoporosis）的发病率持续攀升，亟需开发安全、有效且至关重要的廉价合成代谢治疗手段——鉴于当前医疗保健系统普遍负担过重的现实背景。尽管高强度骨骼负荷具有合成代谢效应且颇具应用前景，但随年龄增长出现的机械转导（mechanotransduction）功能缺陷，会显著削弱老年群体中易于执行的运动干预策略对抗骨质疏松症的疗效。本研究探索并抵消此类年龄相关缺陷的研究思路，受到跨层级尺度的细胞信号传导模式的启发，同时基于一项关键认知：在短暂且罕见的事件中触发的细胞应答，具备对时空维度远端组织重塑实现高精度调控的潜力。在此，我们提出了一种骨细胞间实时钙离子（Ca²+）/活化T细胞核因子（NFAT）信号传导的基于智能体的模型（agent-based model），该模型能够完整描述年轻与衰老动物体内多种负荷刺激诱导的骨膜骨形成过程。该模型预测了衰老过程中骨形成能力下降背后的年龄相关通路改变，进而确定了极具治疗潜力的关键缺陷靶点。基于模型预测结果，我们开展了一项体内干预实验，并首次证实：低剂量环孢素A（Cyclosporin A）联合机械刺激，能够完全恢复衰老骨骼中负荷诱导的骨形成能力。这些临床前研究数据为将该已获批药物与轻度体力活动相结合，作为一种廉价却高效的老年群体骨量增加治疗方案提供了理论依据。我们的分析表明，实时细胞信号传导对下游骨骼针对机械刺激的适应性重塑具有显著影响；而对这类原本难以观测的短暂事件进行计算机模拟（in silico）量化分析，催生了一项具备临床应用潜力的新型干预手段。