Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis

Abstract

The correct formation of synovial joints is essential for proper motion throughout life. Movement-induced forces are critical to creating correctly shaped joints, but it is unclear how cells sense and respond to these mechanical cues. To determine how mechanical stimuli drive joint morphogenesis, we combined experiments on regenerating axolotl forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a TRPV4 agonist to impair chondrocyte mechanosensitivity during joint morphogenesis. We quantified growth and shape in regrown humeri from whole mount light sheet fluorescence images of the regenerated limbs. Results revealed statistically significant differences in morphology and cell proliferation between the two groups, indicating that mechanical stimuli play a role in the shaping of the joint. Local tissue growth in our finite element model was dictated by a biological contribution, proportional to chondrocyte density, and a mechanical one, driven by fluid pore pressure dynamics. Computational predictions agreed with experimental outcomes, suggesting that interstitial pressure might promote local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms and regulatory dynamics involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.