title: Differential effects of altered patterns of movement and strain on joint cell behaviour and skeletal morphogenesis.
abstract: There is increasing evidence that joint shape is a potent predictor of osteoarthritis (OA) risk; yet the cellular events underpinning joint morphogenesis remain unclear. We sought to develop a genetically tractable animal model to study the events controlling joint morphogenesis.
  
  
  
  Zebrafish larvae were subjected to periods of flaccid paralysis, rigid paralysis or hyperactivity. Immunohistochemistry and transgenic reporters were used to monitor changes to muscle and cartilage. Finite Element Models were generated to investigate the mechanical conditions of rigid paralysis. Principal component analysis was used to test variations in skeletal morphology and metrics for shape, orientation and size were applied to describe cell behaviour.
  
  
  
  We show that flaccid and rigid paralysis and hypermobility affect cartilage element and joint shape. We describe differences between flaccid and rigid paralysis in regions showing high principal strain upon muscle contraction. We identify that altered shape and high strain occur in regions of cell differentiation and we show statistically significant changes to cell maturity occur in these regions in paralysed and hypermobile zebrafish.
  
  
  
  While flaccid and rigid paralysis and hypermobility affect skeletal morphogenesis they do so in subtly different ways. We show that some cartilage regions are unaffected in conditions such as rigid paralysis where static force is applied, whereas joint morphogenesis is perturbed by both flaccid and rigid paralysis; suggesting that joints require dynamic movement for accurate morphogenesis. A better understanding of how biomechanics impacts skeletal cell behaviour will improve our understanding of how foetal mechanics shape the developing joint.
authors.affiliation: The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, BS8 1TD, UK. Electronic address: l.brunt@bristol.ac.uk.
authors.forename: L H
authors.initials: LH
authors.lastname: Brunt
authors.affiliation: The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, BS8 1TD, UK. Electronic address: rs9944@bristol.ac.uk.
authors.forename: R E H
authors.initials: RE
authors.lastname: Skinner
authors.affiliation: The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, BS8 1TD, UK. Electronic address: karen.roddy@bristol.ac.uk.
authors.forename: K A
authors.initials: KA
authors.lastname: Roddy
authors.affiliation: The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, BS8 1TD, UK. Electronic address: nataliamdearaujo@gmail.com.
authors.forename: N M
authors.initials: NM
authors.lastname: Araujo
authors.affiliation: School of Earth Sciences, Life Sciences Building, University of Bristol, BS8 1TQ, UK. Electronic address: e.rayfield@bristol.ac.uk.
authors.forename: E J
authors.initials: EJ
authors.lastname: Rayfield
authors.affiliation: The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, BS8 1TD, UK. Electronic address: chrissy.hammond@bristol.ac.uk.
authors.forename: C L
authors.initials: CL
authors.lastname: Hammond
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones; D002356:Cartilage; D009024:Morphogenesis; D009068:Movement; D009119:Muscle Contraction
keywords: Biomechanics; Cells; Hypermobility; Joint morphogenesis; Paralysis; Zebrafish