Chairs
Professor Andrew Pitsillides, The Royal Veterinary College, UK
Dr Chrissy Hammond, University of Bristol, UK
Professor Andrew Pitsillides, The Royal Veterinary College, UK
Andrew Pitsillides is Professor of Skeletal Dynamics in the department of Comparative Biomedical Sciences at The Royal Veterinary College, London. His research explores skeletal mechanobiology across diverse biological settings; from the role of embryo movement in the emergence of skeletal form, to how bones and joints respond to functional/ traumatic load in growth, adulthood and ageing.
Dr Chrissy Hammond, University of Bristol, UK
Dr Chrissy Hammond (CLH) is currently an Arthritis Research UK Fellow, with a proleptic appointment at the University of Bristol. She has worked with animal models of musculoskeletal development for over a decade, holding independent fellowships in the UK and the Netherlands. In 2011 she established a group at Bristol. Her group makes use of the genetic amenability and excellent high resolution imaging options of zebrafish along with computational modelling to unpick the relative contributions of biomechanics and genetics on joint development and homeostasis.
08:30-09:00
Uncovering the mechanistic basis of biomechanical input controlling skeletal development: exploring the interplay with Wnt signalling at the joint
Professor Paula Murphy, Trinity College Dublin, the University of Dublin, Ireland
Abstract
Embryo movement is essential to the formation of a functional skeleton. Using mouse and chick models, the group has previously shown that mechanical forces influence gene regulation and tissue patterning, particularly at developing joints. However, there remains a lack of knowledge of the molecular mechanisms that underpin the influence of mechanical signals.
Wnt signalling is required during skeletal development and is altered under reduced mechanical stimulation. To explore Wnt signalling as a mediator of mechanical input, the expression of Wnt ligand and Fzd receptor genes in the developing skeletal rudiments was profiled. Canonical Wnt activity restricted to the developing joint is reduced under immobilization while over-expression of activated b-catenin or the Wnt antagonist Sfrp3 following electroporation of chick embryo limbs, supports the proposed role for Wnt signalling in mechanoresponsive joint patterning. Two key findings advance our understanding of the interplay between Wnt signalling and mechanical stimuli: firstly, the loss of canonical Wnt activity at the joint shows reciprocal, co-ordinated regulation of Wnt and BMP pathways under mechanical influence. Secondly, this occurs simultaneously with increased expression of several Wnt pathway component genes in a territory peripheral to the joint, identifying the importance of mechanical stimulation on a population of potential joint progenitor cells.
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Professor Paula Murphy, Trinity College Dublin, the University of Dublin, Ireland
Professor Paula Murphy, Trinity College Dublin, the University of Dublin, Ireland
Paula Murphy is Professor in Developmental Biology, in the School of Natural Sciences, Trinity College Dublin, the University of Dublin. She is a developmental biologist interested in the mechanisms that generate spatially organized patterns of tissue differentiation in the developing embryo. A science graduate of Trinity College Dublin, specialising in Genetics, she carried out doctoral research at the University of Edinburgh (MRC Human Genetics Unit) under the supervision of Prof RE Hill on Hox genes. Two Postdoctoral Research Fellowships from the European Molecular Biology Organisation and the Human Frontiers Science Programme provided research experience at the University of Rome (La Sapienza) (1991 – 1993) and the Ecole Normale Superieur, Paris (1993 – 1995), working on muscle and peripheral nervous system development. Following research positions in Oslo and Edinburgh she returned to take up her current post at Trinity College in 2001. In 2008 she was elected Fellow of Trinity College Dublin.
09:00-09:30
New players and concepts in muscoskeletal biomechanics
Professor Elazar Zelzer, Weizmann Institute of Science, Israel
Abstract
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.
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Professor Elazar Zelzer, Weizmann Institute of Science, Israel
Professor Elazar Zelzer, Weizmann Institute of Science, Israel
Professor Zelzer received his MSc in immunology from Ben-Gurion University, Beer-Sheva in 1994 and his PhD in molecular genetics in 1999 from the Weizmann Institute of Science. He conducted his postdoctoral studies in developmental biology, focusing on bone angiogenesis, at Professor Bjorn Olsen’s lab, Harvard Medical School. Professor Zelzer established his lab at the Weizmann Institute in 2004. The main goal of his lab is to decipher the fundamental mechanisms of the development of a complex, integrated system in order to expose the underlying biological principles. Using the limb musculoskeleton and its vasculature as a model system, the group have investigated subjects such as growth coordination and scaling, tissue attachment, cross-tissue regulatory interactions and mechanotransduction.
09:30-10:00
The role of fetal movements in shaping the developing human skeleton
Dr Niamh Nowlan, Imperial College London, UK
Abstract
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.
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Dr Niamh Nowlan, Imperial College London, UK
Dr Niamh Nowlan, Imperial College London, UK
Dr Niamh Nowlan is a Senior Lecturer in the Department of Bioengineering at Imperial College London. Following an undergraduate degree in Computer Engineering and a PhD in Biomechanical Engineering from Trinity College Dublin in Ireland, Dr Nowlan held research fellowships in Boston, USA and Barcelona, Spain. Dr Nowlan has received a number of awards for her research, including a Fulbright Award and the 2016 Bioengineering UK Early Career Scientist Award. She joined Imperial College in 2011, and now leads a research group of 7 full-time researchers. Dr Nowlan's group are working on a range of topics relating to foetal movements and skeletal development, funded by grants from the European Research Council and the Arthritis Research UK and Leverhulme Trust charities.
10:00-10:30
Mechanobiology of embryonic tendon development and regeneration
Professor Catherine K Kuo, University of Rochester, USA
Abstract
Tendons transmit muscle-generated forces to bones to enable skeletal movements and stabilize joint structures. Proper development and maintenance of these extracellular matrix-rich tissues is critical to their demanding physical roles throughout the body. Abnormal tendon formation during embryogenesis is associated with frequently occurring musculoskeletal deformities such as congenital tallipes equino varus. Furthermore, tendons injured postnatally fail to recapitulate development during healing, and instead heal with aberrant matrix composition and organization, resulting in reduced functionality and greater susceptibility to re-injury. The group is interested in understanding how tendon mechanical properties elaborate during normal embryonic development to inform the prevention of tendon-related musculoskeletal birth defects and the enhancement of regenerative postnatal healing. This talk will focus specifically on the novel approaches the group has utilized to characterize the mechanical properties of tendons during embryonic development, and crosslinking mechanisms that have been identified to be critical to this process. Furthermore, the talk will discuss the development of engineered hydrogel systems that mimic the embryonic tendon mechanical microenvironment, enabling study of how dynamic changes in tissue stiffness continuously influence cell behaviours (differentiation, extracellular matrix synthesis, etc.) during development. Finally, the talk will discuss the role of physical movements (eg, kicking) in regulating tendon formation during embryonic development. These findings provide new insights into the crucial roles of mechanics and tissue mechanical properties in new tendon formation.
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Professor Catherine K Kuo, University of Rochester, USA
Professor Catherine K Kuo, University of Rochester, USA
Catherine K Kuo is an Associate Professor in the Department of Biomedical Engineering, the Department of Orthopaedics, and the Center for Musculoskeletal Research at the University of Rochester. She received her BSE in Materials Science and Engineering and PhD in Biomaterials and Macromolecular Science and Engineering from the University of Michigan, and completed her Postdoctoral Fellowship in the Cartilage Biology and Orthopaedics Branch of NIAMS at the NIH. Her research focuses on elucidating mechanically and biochemically driven mechanisms of embryonic tendon development and healing, and using these findings to inform novel stem cell-based tissue engineering and regenerative medicine strategies. Professor Kuo is the recipient of numerous accolades for her research, including the Go:Life Award for Innovation in Research (2015), Stem Cell Research and Therapy Emerging Investigator Award (2015), NSF CAREER Award (2013), and March of Dimes Basil O'Connor Starter Scholar Research Award (2011). Her research has been continuously funded by the National Institutes of Health (NIH), Department of Defense (DoD), National Science Foundation (NSF), March of Dimes Foundation, and Biogen Idec. She serves on the editorial review board for the Journal of Orthopaedic Research and the advisory council for the International Society of Ligaments and Tendons. She is Chair of the ORS Tendon Section Research Committee, ORS Program Committee Regenerative Medicine Topic Co-chair, and ORS Ambassador for the US Northeast.