Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis

Author (s): Comellas, E.; Farkas, J.E.; Kleinberg, G.; Lloyd, K.; Mueller, T.; Duerr, T.J.; Muñoz, J.J.; Monaghan, J.R.; Shefelbine, S.J.
Journal: Proceedings of the Royal Society B

Volume: 289
Date: 2022

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 (Ambystoma mexicanum) 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. We simulated local tissue growth in a finite element model with a biological contribution to growth proportional to chondrocyte density, and a mechanical contribution to growth proportional to fluid pore pressure. Computational predictions agreed with experimental outcomes, suggesting that interstitial
pressure driven from cyclic mechanical stimuli promotes local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms involved
in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.



   author = "E. Comellas, J.E. Farkas, G. Kleinberg, K. Lloyd, T. Mueller, T.J. Duerr, J.J. Mu{\n}oz, J.R. Monaghan, S.J. Shefelbine",
   title = "Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis",
   journal = "Proceedings of the Royal Society B",
   volume = 289,
   number = 20220621,
   pages = "",
   month = ,
   year = "2022",
   note = "",