How do bones acquire their shapes? Establishing a paradigm for the biology and mechanobiology of morphogenesis of synovial joints.

从膝关节的铰链关节，到髋关节的球窝关节，再到颈部和下颌的枢轴关节，关节的形状和功能是密不可分的。在胚胎发育过程中，大多数关节最初是两个相对的软骨表面，在称为形态发生的过程中被塑造成各种各样的形状。关节形状对人类健康有着重要的影响，特别是对先天性疾病和衰老的影响。来自临床条件和动物模型的证据表明，由于胎儿运动的机械力在关节形状成型过程中起着关键作用。对动物模型的研究，包括PI和co-I的研究，已经揭示了胎儿运动引起的机械力影响关节发育中的形状和细胞活动。我们小组最近的工作也使用计算建模技术来证明生物力学刺激模式（如应力和应变）与细胞和组织水平活动之间的关系。然而，我们对关节形态发生的关键驱动因素和决定因素及其最终形状的理解仍然很差，特别是对所涉及的细胞过程的机械调节。由于生物和机械生物学影响之间的复杂相互作用，只有结合实验和计算技术的新方法才能解开这些影响，并揭示控制关节形状发展和改进的范式。因此，本研究的目的是利用机械生物学模拟，基于正常和异常机械条件下的形状和细胞水平数据，提出、测试和优化滑膜关节形状形态发生的生物学和机械生物学范式。提出的研究是及时的；近年来，越来越明显的是，关节形状是长期关节健康的关键因素，特别是对于骨关节炎。产前发育是胎儿形状发育最关键的时期，但有关胎儿运动发育条件的基础科学研究有限；尤其是关节弯曲。这项研究将提供第一个关节生长和形态发生的机制模型，并在两个物种中得到验证，这将使生物物理刺激与细胞事件导致生长或形状变化的假设得到证实。这一新的认识将有利于先天性关节疾病的患者及其护理人员，因为我们将对这些关节疾病产生的原因和方式以及环境因素如何以及何时影响关节形状有更深入的了解。该项目将揭示生物学和力学是如何结合起来塑造发育中的关节的，这对理解健康发育以及产前关节发育异常（包括髋关节发育不良和关节挛缩）的情况具有重要意义。

Joint shape and function are inextricably linked, from the hinge joint of the knee, to the ball and socket of the hip, to the pivot joints of the neck and jaw. Most joints start off as two opposing cartilage surfaces in embryonic development that are moulded into a diverse range of shapes in a process known as morphogenesis. Joint shape has important ramifications for human health, with particular implications for congenital disorders and for aging. Evidence from clinical conditions and from animal models has demonstrated that mechanical forces due to fetal movements play a critical role in the process of moulding joint shapes. Research on animal models, including studies from the PI and co-I, has revealed that mechanical forces due to fetal movements affect shape and cellular activity in developing joints. Recent work from our groups has also used computational modelling techniques to demonstrate the relationship between patterns of biomechanical stimuli (such as stress and strain) and cell-and tissue-level activities. However, we still have a poor understanding of the key drivers and determinants of joint morphogenesis and their final shapes, and in particular of the mechanical modulation of the cellular processes involved. Due to the complex interplay between biological and mechanobiological influences, only a novel approach which combines experimental and computational techniques will be capable of unravelling these influences and reveal the paradigm governing development and refinement of joint shape. Therefore, the objective of this research is to propose, test and optimise a paradigm for the biology and mechanobiology of shape morphogenesis of synovial joints based upon shape-and cell-level data under normal and abnormal mechanical conditions, using a mechanobiological simulation. The proposed research is timely; in recent years it has become increasingly apparent that joint shape is a critical factor for long-term joint health, particularly with respect to osteoarthritis. Prenatal development is the most critical time for shape development, yet there is limited basic science research into developmental conditions relating to fetal movement; particularly arthrogryposis. This research will provide the first mechanistic model of joint growth and morphogenesis, validated for two species, which will enable corroboration of hypotheses relating biophysical stimuli to cellular events leading to growth or changes in shape. This new understanding will benefit patients of congenital joint disorders and their caregivers, as we will have a greater understanding of why and how these joint conditions arise, and of how and when environmental factors influence joint shape. This project will reveal how biology and mechanics combine to shape developing joints, with significance for understanding healthy development, and for conditions involving abnormal prenatal joint development including developmental dysplasia of the hip and arthrogryposis.