The movements of a baby in the womb (fetal movements) are a critical sign of the baby’s health and development. Such movements are also important for development of the baby’s bones and joints. When a baby doesn’t move enough, or their movements are restricted in some way, the shapes of their joints don’t form correctly, leading to conditions such as developmental dysplasia of the hip (where the hip joint is unstable or dislocated) or arthrogryposis, where multiple joints are angled abnormally. There is a link between the mechanical forces caused by fetal movements and the processes by which the skeleton takes its shape, but the mechanisms underlying this relationship are unknown.
In this paper, we found that a particular ion channel called TRPV4 (transient receptor potential cation channel subfamily V member 4) is involved in the response of the growing skeleton to the mechanical forces caused by fetal movements. We discovered this link by blocking activity of TRPV4 in embryonic mouse limbs, and showing that the normal response of the tissues to mechanical loading was eliminated. We also showed that activation of TRPV4 by mechanical loading affects proliferation of cells and the production of matrix in the cartilage, both of which affect growth of the joint.
A fascinating thing about TRPV4 is that when the gene which codes for the TRPV4 protein is mutated, a range of different severe skeletal conditions can occur including lethal metatropic dysplasia, spondylometaphyseal dysplasia (dwarfism), and autosomal dominant brachyolmia. Our study is the first to demonstrate that TRPV4 activity in the developing skeleton is closely linked to the mechanical loading from fetal movements. Drugs aimed at targeting TRPV4 are being trialled for a range of different conditions including osteoarthritis and heart failure, and we believe that our research indicates that TRPV4 may be a valuable target for future therapeutic disease modifying drugs for abnormalities of paediatric skeletal development, particularly when fetal movements are reduced or restricted.
The paper was featured on the Science Advances homepage! Many congratulations to Nidal and all co-authors.
Vivien’s final paper from her PhD was published in eCM (open access link). What we found was that when embryos develop without any skeletal muscle, surprisingly, the effects on the skeleton are less severe over development.
Work by our group and others have shown that when skeletal muscle is absent, bones and joints are abnormal with missing cavitation, abnormally shaped bones, and decreased mineralisation. BUT how these abnormalities progress over time in utero was unknown. We wanted to look at stages not previously characterised in detail, and chose TS24 (around e15.5) and TS27 (around e18.5). Our previous work showed different bones and joints are differentially affected by the lack of muscle, so we also looked at a range of rudiments.
At TS24, we found similar effects of absent muscle to those reported before; abnormal sizes and shapes of all major joints in the limb. BUT, at TS27, the joint shapes were much more normal, with much of the significant differences eliminated.
We looked at cell-level activities in the joints at TS24 and TS27 and found that cell size is a possible mechanism underlying the recovery in joint shape over gestation.
Interestingly, cavitation did not change between the two stages, so when cavitation was abnormal at TS24, it didn’t improve by TS27. Therefore, improvements in shape occurred *despite* absent cavitation in some joints.
Perhaps most surprising was the finding that mineralisation, as all muscleless long bones had significantly less mineralisation at TS24, which was completely recovered by TS27, and even exceeded in some rudiments like the ulna. The big question is how does this recovery in both cartilage growth/shape and mineralisation occur? It’s one we are still answering, so watch the space for follow up!
A baby is stillborn every 16 seconds, leading to heartbreak for more than two million families worldwide per year. Despite advances in care for babies after birth, progress towards reducing the number of stillbirths is lagging behind. Over 50 per cent of stillbirths are associated with a reduction in the baby’s movements in the womb but there is currently no way to track a baby’s movements at home.
Prof Nowlan, together with her collaborators Prof Ravi Vaidyanathan, Prof Christoph Lees & Mr Abhishek Ghosh (Imperial College London) and Prof Fionnuala McAuliffe (UCD) has been awarded a contract as part of Wellcome Leap’s In Utero programme, which aims to create the scalable capacity to measure, model and predict gestational development with a primary goal to reduce stillbirth rates by half. Wellcome Leap is a non-profit organisation founded by the Wellcome Trust to accelerate and increase the number of breakthroughs in human health globally. The team aims to determine how their monitor (called the FM monitor) can be used to measure a baby’s health in the womb. The FM monitor could potentially identify babies who are at risk of stillbirth and will also offer reassurance when the baby is healthy, thereby decreasing the rates of unnecessary induction of labour and early delivery.
To thank our summer student Sophie Oatley and to treat ourselves after a busy schedule of tissue sampling, the extended group went for a nice lunch in the UCD University Club. Best of luck to Sophie as she continues her Biomedical Engineering studies in the University of Cambridge!
Jo‘s first first-author paper entitled “Growth orientations, rather than heterogeneous growth rates, dominate jaw joint morphogenesis in the larval zebrafish” was published in the Journal of Anatomy. Read the paper online here (open access).
In this research, a collaboration with Dr Chrissy Hammond (Bristol, UK), we tackle a long running question: what cell activities determine embryonic joint growth & shape?
We tracked individual cells in 3D in the larval zebrafish jaw joint over a 48-hour window. Using changes between cell centroids, we constructed growth maps of rate and direction of local tissue deformations
Growth maps varied substantially in growth orientation and growth rates both spatially at each developmental time point, and over the duration of development studied.
We synthesised the growth rates in a finite element analysis simulation, which was able to accurately predict joint morphogenesis. What this means is that cell positional information (i.e., orientation and volume) over time is enough to approximate growth and shape change. Then, we were able to use the simulation to test the importance of growth orientation, versus heterogeneous growth rates. We found that growth orientation was much more important for shape than growth rate heterogeneity.
Thank-you to the Anatomical Society for funding Jo’s PhD and congratulations Jo and all the team on a lovely study and paper!
Many congratulations to Yuming who passed his PhD viva (pending minor corrections) last week! Many thanks to examiners Dr Yanlan Mao and Dr Naomi Nakayama. It was so lovely to celebrate together as a group and in person after so long without being able to mark occasions properly.
Niamh presented a seminar entitled “How to Grow an Elbow” in the Department of Bioengineering at Imperial College London on the 9th of March, in the company of all the featured researchers (James, Jo, Nidal and Yuming). The seminar is available to view online on YouTube.
Nidal was awarded the prestigious New Investigator Recognition Award (NIRA) from the Orthopaedic Research Society (ORS) at their 2022 Annual Meeting in Tampa, Florida, USA. NIRA finalists present a poster and give a podium presentation and are interviewed by the NIRA committee, and award recipients chosen based on quality and presentation of material. Awardees receive a certificate and a generous cash prize. Many congratulations Nidal on the fantastic achievement!
Funding is available for a fully funded PhD position in UCD in Ireland from May or September 2022. This PhD project will investigate how mechanical loading affects postnatal development of articular cartilage in a goat model system. The research will involve an exciting combination of biological, imaging and engineering techniques. There will be opportunities for international travel and collaboration.
Candidates can be from anywhere in the world. The project will be in close collaboration with the UCD Veterinary School and co-supervised by Prof Nowlan and by Prof Pieter Brama. The studentship includes stipend of €18,000 per annum (tax free) and fees (EU or international). Funding is available for four years.
Applicants should have a first class or upper second class degree (ideally a Masters) in Biomedical Engineering, Biomedical Science, Medical or Veterinary Sciences, or a closely related discipline. Candidates should have a keen interest in working with translational animal models, and also in the biomechanics of the musculoskeletal system.
To apply, please send a CV and a cover letter summarising your experience and your interests in this specific PhD project to Prof Nowlan. The position is open until filled. Come join us at UCD!