Cyclical compression loading is the dominant mechanoregulator of synovial joint morphogenesis

Mechanical stimuli arising from fetal movements are critical factors underlying joint growth. Abnormal fetal movements negatively affect joint shape features with important implications for joint function and health, but the mechanisms by which mechanical forces due to fetal movements influence joint growth are still unclear. In this research, we integrated cell-level data into a novel mechanobiological model of zebrafish jaw joint morphogenesis to identify links between the mechanical stimuli arising from movement and patterns of growth. Larval zebrafish jaw joint growth patterns were quantified from tracked cell-data at several successive developmental stages in the presence or absence of movements. Pharmacological immobilisation, prior to the onset of jaw movements, resulted in growth rate decreases which were stronger along the ventrodorsal axis. Simulations of joint morphogenesis, based on the quantified cell-level data and which integrated mechanical stimuli arising from simulated jaw movements, were used to test hypotheses relating specific mechanical stimuli with the local changes in size and shape. Different types of mechanical stimulation were incorporated into the simulation to provide the mechanoregulated component on growth in addition to the baseline (non mechanoregulated) growth which occurs in the immobilised animals. We found that the magnitude of compression experienced during joint motion when included as the stimulus for mechanoregulated growth could not predict the real, normally loaded shaped joints. However, when the dynamic changes caused by the application of cyclical compression was implemented as the stimulus for mechanoregulated growth, the sizes and shapes of joints were correctly simulated. We conclude therefore that the cyclical application of compression loading due to the dynamic nature of fetal movements underlies the mechanoregulation of prenatal joint morphogenesis. Our results provide a fundamental advance in our understanding of mechanoregulation of the developing joint and increase our understanding of the origins of conditions such as hip dysplasia and arthrogryposis. Author summary The mechanical forces caused by fetal movements are important for normal development of the skeleton, and in particular for joint shape. Several common developmental musculoskeletal conditions such as developmental dysplasia of the hip and arthrogryposis are associated with reduced or restricted fetal movements. Paediatric joint malformations impair joint function and can be debilitating. To understand the origins of such conditions, it is essential to understand how the mechanical forces arising from movements influence joint growth and shape. In this research, we used a computational model of joint growth applied to the zebrafish jaw joint to study the impact of fetal movements on joint growth and shape. We find that the cyclical application of compression loading is critical to the normal growth and shape of the developing joint. Our findings implicate that dynamic compression must be targeted when developing strategies for the treatment of musculoskeletal conditions through targeted physiotherapy.