Development of an in vitro musculoskeletal model of human ageing

在全球范围内，肌肉骨骼（MSK）疾病是导致残疾的主要原因，通常与抑郁和对生活质量的负面影响有关。MSK疾病在全球范围内具有重大的经济影响，随着全球人口日益老龄化，其患病率预计将上升。目前，MSK的药物治疗是通过单培养筛选的，或者充其量是体外单层细胞的共培养。然而，组织内的细胞-细胞和细胞-基质相互作用，以及这些组织在肌肉、骨骼和软骨之间的界面处不同的机械和结构特性，意味着单层模型无法捕捉这些相互作用。MSK老化也会引起细胞外基质的变化，但简单的二维单培养不能以任何有意义的方式再现这些变化。因此，研究人员经常求助于动物模型。然而，在大小、解剖结构和生物力学方面的重要差异限制了它们的相关性，并阻碍了MSK药物开发的成功结果。文献中已经描述了开发3D模型的尝试，但这一领域的成功受到许多版本的限制，这些版本仅包含来自一种组织类型的细胞，因此忽略了细胞类型之间的相互作用。因此，对可靠的、生物学相关的MSK界面体外模型的需求尚未得到满足，该模型可以减少和取代动物模型，反映衰老过程，从而加速MSK治疗的发展。

Globally, musculoskeletal (MSK) conditions are the leading contributor to disability and are commonly linked with depression and negative impacts on quality of life. MSK conditions have a significant economic impact worldwide and their prevalence is predicted to rise with an increasingly ageing global population.Currently drug treatments for MSK conditions are screened using monocultures or, at best, co-cultures of cells growing in monolayers in vitro. However, the cell-cell and cell-matrix interactions within the tissues together with the differing mechanical and structural properties of these tissues at the interface between muscle, bone and cartilage mean that monolayer models fail to capture these interactions. MSK ageing also induces extracellular matrix changes but simple 2D monocultures are incapable of recapitulating these changes in any meaningful way. As a consequence, researchers often turn to animal models. However, important differences in size, anatomy and biomechanics limit their relevance and hinder successful outcomes in the MSK drug development. Attempts to develop 3D models have been described in the literature, but success in this area is limited with many versions incorporating the cells from only one tissue type and therefore omitting the interactions between cell types. There is therefore an unmet need for a reliable, biologically relevant in vitro model of the MSK interface that can reduce and replace animal models, reflect the ageing process and thereby accelerate the development of MSK treatments.