Compressive stress gradients direct mechanoregulation of anisotropic growth in the zebrafish jaw joint.

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 health, but the mechanisms by which mechanical forces from fetal movements influence joint growth are still unclear. In this research, we quantify zebrafish jaw joint growth in 3D in free-to-move and immobilised fish larvae between four and five days post fertilisation. We found that the main changes in size and shape in normally moving fish were in the ventrodorsal axis, while growth anisotropy was lost in the immobilised larvae. We next sought to determine the cell level activities underlying mechanoregulated growth anisotropy by tracking individual cells in the presence or absence of jaw movements, finding that the most dramatic changes in growth rates due to jaw immobility were in the ventrodorsal axis. Finally, we implemented mechanobiological simulations of joint growth with which we tested hypotheses relating specific mechanical stimuli to mechanoregulated growth anisotropy. Different types of mechanical stimulation were incorporated into the simulation to provide the mechanoregulated component of growth, in addition to the baseline (non-mechanoregulated) growth which occurs in the immobilised animals. We found that when average tissue stress over the opening and closing cycle of the joint was used as the stimulus for mechanoregulated growth, joint morphogenesis was not accurately predicted. Predictions were improved when using the stress gradients along the rudiment axes (i.e., the variation in magnitude of compression to magnitude of tension between local regions). However, the most accurate predictions were obtained when using the compressive stress gradients (i.e., the variation in compressive stress magnitude) along the rudiment axes. We conclude therefore that the dominant biophysical stimulus contributing to growth anisotropy during early joint development is the gradient of compressive stress experienced along the growth axes under cyclical loading. 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. We find that how the amount of compressive loading changes along the rudiment axes and over the loading cycle is critical to the normal growth of the developing joint. Our findings implicate gradients of compressive loading as a promising target when developing therapeutic strategies (such as targeted physiotherapy) for the treatment of musculoskeletal conditions. [ABSTRACT FROM AUTHOR]