Mechanosensitivity of osteoporotic stem cells for diagnosis and treatment of osteoporosis

骨质疏松干细胞的机械敏感性用于骨质疏松症的诊断和治疗

• 批准号: 2745304
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2745304
• 关键词: Mechanosensitivity; osteoporotic; stem; cells; diagnosis

Osteoporosis is the most common bone disease in humans, affecting over a quarter of people aged 50+ years. The condition predominantly affects post-menopausal women and results in over 500,000 fragility related fractures p/a within the UK. The elevated fracture risk from everyday activities, due to weakened bones, is a major challenge for our aging population. Current pharmaceutical treatment options, such as bisphosphonates, are proving insufficient to provide long term fracture protection. To ensure bone health into older age, new treatment modalities are required, representing an opportunity for bioengineering strategies. Mechanical loading is a key factor in maintaining bone health. Homeostasis of bone density is a result of balance in the activities of osteoblasts and osteoclasts, which are both mechanically sensitive. A lack of loading (e.g. during zero-g spaceflight or extended bed rest) has been show to result in increased bone resorption and a loss of bone density. In age-related osteoporosis, the disease is not necessarily due to a lack of loading per se, but can be a failure of bone cells to respond sufficiently to mechanical signals. Therefore, one resulting hypothesis is that osteoporosis directly results from altered mechanotransductive signalling mechanisms at the cellular level.Prior research has focussed on methods of mechanically stimulating cells in vitro, such as the use of nanoamplitude vibration. The use of certain vibration parameters (1 kHz, 30 nm amplitude) has shown effective osteogenic stimulation of adult mesenchymal stem cells (MSCs) derived from bone marrow and adipose tissue. This stimulation method includes activation of mechanotransductive pathways via ROCK signalling and mechanosensitive ion channels with a potential dependence on vibration amplitude. The process alters focal adhesion conformation and increases cellular tension through increased actin-myosin contractility, potentially also changing cellular mechanical properties as measured by in vitro techniques (e.g. AFM, cell deformation). In the case of MSCs, this leads to differentiation towards a high contractility osteoblastic phenotype and increased mineralisation, without recourse to osteogenic reagents or growth factors. However, the differences in mechanotransductive response between healthy and aged/osteoporotic MSCs are yet to be studied. Alongside in vitro cell stimulation studies, development of wearable devices which can apply nanovibration directly to patients has begun. Before this technology can be applied to the clinical challenge of osteoporosis, there needs to be further understanding of the mechanotransductive response of osteoporotic bone cells compared to healthy osteogenic cells residing within the bone marrow cavity. In addition, the identification of suitable administration options for a vibrational therapy (in terms of duration, amplitude and frequency) may need to be reconsidered for bone cells in the diseased state.RESEARCH OBJECTIVES1. To study phenotypic changes of osteoporotic stem cells under various levels of mechanical loading across different age groups.2. To determine if cellular mechanical properties (e.g. stiffness, deformability) could be used as a diagnostic of bone forming capacity and onset of osteoporosis or reduced mechanotransductive signalling.3. Use in vitro data to develop therapeutic nanovibration protocols which could be applied practically via wearable vibration devices

骨质疏松症是人类最常见的骨骼疾病，影响超过四分之一的50岁以上人群。这种情况主要影响绝经后妇女，导致英国超过50万例脆性相关骨折。由于骨骼变弱，日常活动导致骨折风险增加，这是老龄化人口面临的主要挑战。目前的药物治疗方案，如双膦酸盐，被证明不足以提供长期的骨折保护。为了确保骨骼健康进入老年，需要新的治疗方式，这代表了生物工程策略的机会。机械负荷是维持骨骼健康的关键因素。骨密度的动态平衡是成骨细胞和破骨细胞活动平衡的结果，它们都是机械敏感的。缺乏载荷（例如在零重力太空飞行或长时间卧床休息期间）已被证明会导致骨吸收增加和骨密度损失。在与年龄相关的骨质疏松症中，这种疾病不一定是由于缺乏载荷本身，但可能是骨细胞对机械信号的反应不足。因此，一个由此产生的假设是骨质疏松症直接由细胞水平上机械转导信号机制的改变引起。先前的研究主要集中在体外机械刺激细胞的方法上，例如使用纳米振幅振动。使用一定的振动参数（1 kHz， 30 nm振幅）已经显示出对来自骨髓和脂肪组织的成体间充质干细胞（MSCs）的有效成骨刺激。这种刺激方法包括通过ROCK信号和机械敏感离子通道激活机械转导通路，这些通道与振动幅度有潜在的依赖性。这一过程通过增加肌动蛋白-肌球蛋白的收缩性，改变了局部黏附构象，增加了细胞张力，也潜在地改变了体外技术（如AFM，细胞变形）测量的细胞力学特性。在MSCs的情况下，这导致向高收缩性成骨细胞表型分化和矿化增加，而不依赖成骨试剂或生长因子。然而，健康和老年/骨质疏松间充质干细胞在机械转导反应上的差异还有待研究。除了体外细胞刺激研究外，可穿戴设备的开发也已经开始，该设备可以直接将纳米振动应用于患者。在这项技术应用于骨质疏松症的临床挑战之前，需要进一步了解骨质疏松性骨细胞与骨髓腔内健康成骨细胞的机械转导反应。此外，对于处于病变状态的骨细胞，可能需要重新考虑振动治疗的合适给药选择（在持续时间、振幅和频率方面）。研究OBJECTIVES1。研究不同年龄群体骨质疏松干细胞在不同机械负荷水平下的表型变化。2 .确定细胞力学特性（如刚度、可变形性）是否可作为骨形成能力和骨质疏松症发病或机械传导信号减少的诊断指标。利用体外数据开发可穿戴振动装置实际应用的治疗性纳米振动方案