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In genetic language, achondroplasia is an autosomal dominant condition which may be inherited or inborn. What this means is that the gene responsible for achondroplasia lies on a chromosome that is neither X or Y chromosome, that one needs only one copy of that gene mutated to have achondroplasia, and that parents who both have normal statures can give birth to a baby with achondroplasia.

In growing long bones, such as those found in the arms and legs, there are two types of tissue – bone (which is the hard, mineralized portion) and cartilage (which is the softer, elastic portion). All long bones begin as a cartilage tissue, where specialized cells, called chondrocytes, divide, lay down a specific kind of extracellular matrix and enlarge – all these three processes contribute to growth. Evolutionary speaking, humans need to grow rapidly after birth, simply because, historically, there were many other organisms around that were bigger and tried to eat us. The ability to survive in such hostile environment dictated a rapid postnatal growth. Today these predators are no longer a threat, but we still grow rapidly after birth. However, within our terrestrial environment, the advantage of growing quickly early in life is also outweighed by many disadvantages of growing too large (these disadvantages start showing themselves when someone is taller than approximately 190 cm). Therefore, evolution has programmed our bodies to stop growing when we reach maturity around 18 years of age. This is different compared to water animals – because water supports an increasing body weight much better than air. For many water animals the advantage of getting bigger remains good for life – this is why fish continue growing for most of their life.

But back to humans with their restricted growth. We stop growing because our brain ceases to produce growth hormone. Growth hormone can cause cells to divide and also acts as a survival factor for chondrocytes. Being a chondrocyte is a tough job, one has to divide and make matrix for many years in the environment with is poor in nutrients and oxygen – growing cartilage contains no blood vessels, which limits supply of nutrients and oxygen. Another adversary is the bone tissue itself. Bone cells continuously replace cartilage in the growing skeleton. When our bodies cease to produce growth hormone, the growing cartilage disappears and is replaced by bone. This is why our bones cannot restart their growth later in life, there is no growing cartilage left. Apart from the central growth regulation mediated by growth hormone produced by our brains, there are many other molecules that regulate cartilage growth locally, i.e. they are produced in cartilage and act on cartilage. One of the major negative regulators is FGFR3, the gene that is affected in achondroplasia.

FGFR3, or fibroblast growth factor receptor 3, in its normal function acts as a brake on growth, making sure that our bones lengthen just enough and not too much. Mechanistically, FGFR3 is a receptor for a communication signal called FGF, or fibroblast growth factor. FGF delivers its signal to chondrocyte, which instructs the chondrocyte to stop growing or grow less. One can imagine this communication between chondrocytes simply resembles a human language. The tool of communication is the spoken word, and we have ears to listen and understand to what others have to tell us. In growing cartilage, the FGF is the word, and FGFR3 is the ear on the surface of the chondrocyte which it uses to ‘hear’ the message FGF is trying to deliver. The problem in achondroplasia is that FGFR3 contains a mutation that makes it more sensitive. Therefore, its response to the FGF signal is increased just as if you have sensitive hearing, you will hear more sounds. In cartilage, the message delivered by FGF to chondrocytes is ‘do not grow’. Normally this restricts chondrocyte growth just a bit. But when the FGFR3 is more sensitive, it ‘hears’ more the FGF. As a result, chondrocytes grow less than normal. Ultimately, this leads to short stature and other malformations associated with achondroplasia.

The pathological FGFR3 function in achondroplasia may be fixed, and if we do so successfully we will find the cure for achondroplasia. Several kinds of research are being done to accomplish that. The basic research on achondroplasia tries to understand the basic mechanics of how FGFR3 affects chondrocyte behavior. There are many other protein molecules involved in the regulation of chondrocyte by FGFR3, and scientists are trying to identify them and understand their function. Clinical research, on the other hand, tries to understand the manifestations of achondroplasia at the level of entire organism, e.g. the patient. Positioned between the two is the research on development of drugs which inhibit FGFR3 or other molecules it uses to regulate chondrocyte behavior, in order to reverse FGFR3 effects on chondrocyte. We first have to understand how FGFR3 works, than discover or invent molecules which inhibit FGFR3 function, and finally, successfully apply those molecules in clinical achondroplasia treatment. As with many other conditions, the quest for achondroplasia treatment is a complex and difficult journey which requires continuous effort of scientists from many different fields.