Nidal & team’s TRPV4 paper published in Science Advances

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.

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