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

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.