Abstract
SummaryObjectiveThere 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.DesignZebrafish 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.ResultsWe 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.ConclusionWhile 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.
Highlights
We understand that the mechanical environment experienced during early development is important for normal skeletal development
Few studies have focused on the role of biomechanics in craniofacial development, though craniofacial morphogenesis is affected by paralysis, with different joints differentially affected in chicks[13,16,17]
In this paper we explored the differences and similarities in skeletal development under continuous or absent muscle load compared with control and hyperactive zebrafish
Summary
We understand that the mechanical environment experienced during early development is important for normal skeletal development. There is evidence that early changes to joint shape lead to osteoarthritis (OA) later in life[6] This can arise if conditions such as DDH are uncorrected[7], and subtle changes to hip shape have been identified as conferring increased risk of OA8,9. Few studies have focused on the role of biomechanics in craniofacial development, though craniofacial morphogenesis is affected by paralysis, with different joints differentially affected in chicks[13,16,17] It is less clear what the effect of more sustained hyperactivity of the system will be and whether this would be beneficial to the skeletal system; for example, in chick, the effects of hypermobility have been described to increase joint cavity size[18]
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