Like everything in the body, the shape, size and construction of the skeleton is largely determined by the plan laid down by the genes. So, if there are changes in the genes that regulate bone growth, then there is a high chance that there will be changes in the skeleton too. There are hundreds of skeletal disorders that have been traced back to genetic factors. These range from brittle bones to bowed bones.
or shortened limbs. While still rare, achondroplasia is the most common of these genetic skeletal disorders, occurring in around 1 in 25,000 live births. While the disease affects nearly all the bones in the body, it is most obvious in the limbs, and on average, people with achondroplasia will end up around 25% shorter than people of average height. To understand why this happens, We have to take a closer look at how bones grow.
In people, there are two different ways that bones form, but the type of growth that is affected in achondroplasia is called endochondral bone growth. This is the main sort of growth responsible for lengthening bones, and it only occurs in specific places around the body, called the cartilage growth plates. If we look within these growth plates, we see that a special sort of cartilage is growing and being replaced by bone. So, if something slows this process down, this can result in abnormalities in the length and shape of the bones. And because these plates are the source of bone growth almost everywhere in the body, changes that slow down this growth result in shorter bones everywhere.
Diving inside this growth plate, we can get a better understanding for exactly how this process happens. Looking closely we can see that the growth plate is actually made of thousands of individual cartilage cells carefully stacked in layers. At the top of the plate the cartilage cells divide, below that they grow larger, then mature and are finally replaced by bone cells moving in from below.
As each new layer of bone forms at the bottom More cells are dividing and growing at the top, adding layer upon layer of bone at the edge of the growth plate. It's just like how a brick layer builds up a wall, one row at a time. To ensure this process happens in a perfectly organised way, there are a huge number of signals that regulate how fast and where this growth happens. The signals themselves are often small molecules circulating around the body, and the cells in these layers...
need a way to read and respond to them. On each cell, this process usually starts with what's known as a receptor, a special molecule that pokes through the cell surface and recognizes these signals. The combination of hundreds of different signals being recognized across millions of cells is what controls how, when, and where bones grow. However, in people with achondroplasia, The gene for one of the key receptors in regulating cartilage cell growth is altered, the fibroblast growth factor 3 receptor, or FGFR3.
To understand exactly how changes in the FGFR3 gene cause bone growth to slow down and see how it interacts with some of the other growth controls, we have to look inside the cell. The FGFR3 molecule is embedded in the surface on these cells with one side sticking out to sense the passing signals and the other side facing in to tell the rest of the cell what it's seen. Normally, the receptor is only activated when it joins with a specific signaling molecule on the outside called a fibroblast growth factor or FGF.
These FGF molecules fit into their receptors like a lock going into a key. When one of these FGF molecules slots into the receptor, It causes a change in the same receptor on the inside, setting off a chain of signals that tells the cell to stop growing. It's the FGF signal sticking on the outside that sets off the stoplights for growth on the inside of the cell. This is a normal process throughout the body, where signaling via these FGF molecules helps to regulate the formation of the skeleton.
In someone with achondroplasia, A change in the gene for the FGFR3 receptor means that it's active, even without an FGF molecule being in position on the outside. This means the growth traffic light is stuck in the stop position, regardless of what signals FGFR3 sees outside. And because FGFR3 is regulating bone growth in these cartilage cells throughout the body, it doesn't just mean that bones in the arm are shorter, it means all bones with growth plates are shorter. and some can end up misshapen.
In fact, the gene for FGFR3 is present everywhere in the body, and while what it does outside of these growth plates isn't fully understood, it is very likely that this overactivity is responsible for some of the other associated conditions seen in people with achondroplasia. Alongside this FGF system, there are many other components that control bone growth too. But one of the most important is a receptor called NPRB, which responds to a different signal from outside the cell, a molecule called CNP.
When NPRB has CNP in position on the outside, it acts as a go switch for bone growth by turning off the stop signal coming from FGFR3. So, when CNP is present on the outside of the cell, this additional signal silences the stop signal from FGFR3, allowing the cartilage cells to grow again and the bones to get longer. Again, this is a normal process, and this balance between the FGFR3 and CNP-NPRB pathways is one of the things that helps to fine-tune bone growth.
In people with achondroplasia, the signals from the FGFR3 receptors are generally stronger. Overriding the go signal from CNP. But what is particularly interesting about the CNP system is that it might give scientists a way to restore the balance between the two pathways in people with achondroplasia and release that bone growth stop signal.
Understanding the details of how our genes impact the development of our skeletons is beginning to unlock the secrets of our bodies. And the more the scientific community learn about these processes, the closer they get to understanding bone growth disorders.