Finite element modelling predicts changes in joint shape and cell behaviour due to loss of muscle strain in jaw development

Abnormal joint morphogenesis is linked to clinical conditions such as Developmental Dysplasia of the Hip (DDH) and to osteoarthritis (OA). Muscle activity is known to be important during the developmental process of joint morphogenesis. However, less is known about how this mechanical stimulus affects the behaviour of joint cells to generate altered morphology. Using zebrafish, in which we can image all joint musculoskeletal tissues at high resolution, we show that removal of muscle activity through anaesthetisation or genetic manipulation causes a change to the shape of the joint between the Meckel's cartilage and Palatoquadrate (the jaw joint), such that the joint develops asymmetrically leading to an overlap of the cartilage elements on the medial side which inhibits normal joint function. We identify the time during which muscle activity is critical to produce a normal joint. Using Finite Element Analysis (FEA), to model the strains exerted by muscle on the skeletal elements, we identify that minimum principal strains are located at the medial region of the joint and interzone during mouth opening. Then, by studying the cells immediately proximal to the joint, we demonstrate that biomechanical strain regulates cell orientation within the developing joint, such that when muscle-induced strain is removed, cells on the medial side of the joint notably change their orientation. Together, these data show that biomechanical forces are required to establish symmetry in the joint during development.