Uncovering the mechanistic basis of biomechanical input controlling skeletal development
Professor Paula Murphy, Trinity College Dublin, the University of Dublin, Ireland
New players and concepts in muscoskeletal biomechanics
Professor Elazar Zelzer, Weizmann Institute of Science, Israel
Muscle spindles and Golgi tendon organs (GTOs), proprioceptive mechanoreceptors located inside striated muscles and in myotendinous junctions, respectively, are components of the stretch reflex circuitry that control muscle activity. Using genetic mouse models, the group demonstrates the involvement of proprioception in regulating spine alignment and spontaneous realignment of fractured bones, dubbed natural reduction. Failure of the mechanism that maintains posture may result in spinal deformity as in adolescent idiopathic scoliosis. The group shows that null mutants for Runx3 transcription factor, which lack connectivity between proprioceptors and spinal cord, developed peripubertal scoliosis not preceded by vertebral dysplasia or muscle asymmetry. Deletion of Runx3 in the peripheral nervous system or specifically in peripheral sensory neurons, or of enhancer elements driving Runx3 expression in proprioceptive neurons, induced a similar phenotype. Egr3 knockout mice, lacking spindles but not GTOs, displayed a less severe phenotype, suggesting that both receptor types are required for this regulatory mechanism.
Fracture repair involves restoration of bone morphology. Comparison among mice of different ages revealed, surprisingly, that three-month-old mice exhibited more rapid and effective natural reduction than newborns. Fractured bones of Runx3-null mutants failed to realign properly. Blocking Runx3 expression in peripheral nervous system, but not in limb mesenchyme, recapitulated the null phenotype, as did inactivation of muscles flanking the fracture site. Egr3 knockout mice displayed a less severe phenotype, suggesting that both receptor types, as well as muscle contraction, are required for this regulatory mechanism. Overall, these findings uncover physiological roles for proprioception in non-autonomous regulation of skeletal integrity and repair.
The role of fetal movements in shaping the developing human skeleton
Dr Niamh Nowlan, Imperial College London, UK
Mechanical stimulation generated by fetal kicking and movements is known to be important for prenatal musculoskeletal development, and there are a number of human conditions that emphasise the link between abnormal fetal movements and delayed or impaired skeletal development. The most common of these is developmental dysplasia of the hip (DDH), a relatively common joint shape abnormality (clinical incidence 1.3 in 1000), the risk of which is strongly associated with restricted fetal movement, such as fetal breech position. The group is using computational modelling approaches (finite element analysis and musculoskeletal modelling), combined with human fetal imaging data to try to understand how the biomechanical stimulation (stresses and strains) caused by fetal movements evolve in the prenatal developing hip joint. Furthermore, the group models a range of intra-uterine conditions and situations that increase the risk of DDH, such as fetal breech position and oligohydramnios (reduced amniotic fluid), in order to be able to understand how a range of factors affecting movement may impact on the developing hip joint.
Talk title tbc
Professor Catherine K Kuo, University of Rochester, USA