I am not a mother myself, but I imagine having a tiny human kicking and moving around in your womb can feel quite uncomfortable. At some point, you may, out of frustration, wonder: why do they move around so much?! A research group co-led by Paula Murphy from Trinity College Dublin has been able to provide the answer: to develop the joints. Based on observing clinical conditions where movement is restricted or limited, scientists postulate that movement and mechanical forces are required for joint development and maintenance in adults. However, little is known about the molecular details of how this works. This group in Dublin is the first to identify key pathways involved in the mechanosensing aspect of joint development.

These findings do not just concern expecting parents or science enthusiasts. With an ageing population and an ever-increasing number of individuals suffering from joint diseases, regenerative medicine offers an attractive option to treat joint problems. By identifying key molecular developmental cues, we could be a step closer to bringing this technology to the clinic.

Regenerative medicine, namely the use of stem cells, is used to regenerate or repair damaged tissues. Following cell development, they turn into a specific cell type, for example cartilage. Scientists have been able to do just this by mimicking the natural process of development.

During development, the embryo matures and undergoes a process called differentiation, meaning the cells become specialised into different types, which carry out a particular function. In the process of differentiation – whether it is during development or in the lab – cells require precise and accurate communication with each other. Imagine the game of Telephone, where the objective of the game is to pass a message along the entire group without distorting it. As a child, the final statements are often hilariously divergent due to the accumulation of errors. However, if this happens to differentiating cells, a deformed body can result. Comparatively, cells perform much better than us, as multiple complex communication systems are used to ensure the right cell receives the right message.

“Why do foetuses move so much? To develop their joints!”

Humans use words and body language to communicate, whereas cells use signals. Molecular signals and mechanical stress can be perceived by a cell such that they respond accordingly. As mentioned, in the case of cartilage cells, which are fundamental building blocks that makes up your joints, mechanical stimulation is important. In previous research, mouse and chick embryos that had their movement restricted had an abnormal distribution of cartilage cells across the joint region. With this new research, the molecular pathway that responded to this mechanical stress has now been identified.

By studying gene expression profiles of animals that were immobilised in the embryo during the developmental stage, a few molecular pathways – namely the canonical Wnt and BMP signalling – were highlighted to be instrumental. In particular, the regulation of these pathways modulates expression of genes that allow cells to sense the mechanical stimuli around them, and/or drive differentiation to a cartilage lineage. For instance, Smurf1 is shown to create a permissive environment for appropriate cartilage differentiation. Furthermore, genetic knockout studies have shown the activation of canonical Wnt is essential for normal joint development. This evidence reported that along with the reduction of Wnt signalling, the lack of movement causes the ectopic activation of BMP signalling via the down-regulation of Smurf1/2, and is pivotal to joint development.

While the study was conducted on chickens and mice, it is likely that this mechanism is evolutionarily conserved across vertebrates. Consequently, there is a high probability that such findings are applicable to humans, both in terms of understanding congenital defects and developing regenerative therapies for joint diseases.