Author: nowlann

Nidal’s paper entitled “Mechanoregulatory role of TRPV4 in prenatal skeletal development” was published in leading journal Science Advances! The project was a fantastic team effort from Nidal, James, Yuming and Saima, together with collaborator in Trinity College Dublin David Hoey. This work was supported by European Research Council under the European Union’s Seventh Framework Program, ERC Grant agreement number 336306

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!

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!