Sunday, February 19, 2012

Reducing FGFR3 influence in achondroplasia, part 4

We have been following the fibroblast growth factor receptor 3 (FGFR3) to find where it would be possible to interfere in its activity in order to counteract the negative effects this receptor produces in achondroplasia (ACH).

We have explored the extracellular part (domain) of the receptor, where aptamers could be developed to block the FGFs’ docking site. We crossed the chondrocyte cell membrane to look at what is called the transmembrane domain where short peptides – called transmembrane interceptors – could be created to hinder the dimmer formation.
We also learned about closing the active areas of FGFR3 in its intracellular domain by specific drugs, the tyrosine kinase inhibitors (TKIs). Closing the FGFR3 electric plugs by TKIs will halt the entire electric/chemical signaling cascade. The expected consequence is that the chondrocytes will be able to proliferate more, get mature (hypertrophic) and give space for bone, restoring a normal (or near normal) bone growth.
Now, let’s go downstream into the signaling cascade.
We can think in FGFR3 signaling cascade like a domino chain. When the first piece is pushed against the second, the entire row will follow, one after another in a chain reaction. In our case, FGFR3 is the first piece of the row and, once activated it will trigger other domino pieces, or other enzymes. Now, think what would happen if we took one or two pieces from the middle of the domino chain. The signal initiated by FGFR3 would not reach its targets inside the cell nucleus thus not causing the effects it is responsible for.
In the last decade, researchers have learned about how FGFR3 influences bone growth by blocking what they believed were its signaling cascades. That’s how we know today which enzymes are relevant for FGFR3. Take a look in this Dr. Horton’s review for a figure showing the cascade. Simplifying a lot, we could describe one of the most relevant FGFR3 chains like this:

FGFR3 > FRS2a/SOS/Grb > Ras > Raf > MEK > ERK/p38 > Nucleus

The other important one is shorter:
FGFR3 > STAT1 > Nucleus

Each of the above acronyms represents an enzyme (or, by analogy, a domino piece).
In theory, we could stop the FGFR3 signaling blocking any enzyme located in this domino chain. Tests have been performed with different enzyme inhibition methods and results confirm the relevance of these enzymes for bone growth. For instance, this study showed that ERK1 and ERK2 inhibition restored bone growth and rescued spine stenosis (enlarged the spinal canal) in an animal model. 

The higher the position in the domino chain, the broader would be the effect of this blockage. On the other side, the lower in the domino chain, the more specific would be the effect of taking out a domino piece.
However, inhibiting enzymes downstream of FGFR3 is not that simple. The enzymes that respond to FGFR3 activation react also to several other receptors, including the other FGFRs (reviewed in a previous post). In other words, there is a risk that blocking, for instance, the RAF enzyme, we would face secondary effects due to the blockage of other receptors’ signaling. This certainly would not be good in a growing body of a child. The risk exists because although FGFR3 is produced almost exclusively by chondrocytes, the enzymes of the domino chain are produced by many other cells in other tissues. What would happen if we gave an anti-ERK aiming to treat ACH? What kind of effects in other cells and, by extension, in other tissues and organs of the body could we expect?

In a child with ACH everything is normal, but a single protein (FGFR3) produced by an unique kind of cell (the chondrocyte), located in a very special tissue (the growth plate cartilage). Taking together the current knowledge about FGFR3 and how it functions, it makes more sense to target FGFR3 directly than other enzymes in its signaling pathway.
In summary, we have reviewed in this series of posts where we could interfere in the function of FGFR3 to reduce its activity in a way that could restore, even partially, the bone growth. So far, there are at least three different potential approaches: the aptamers, the transmembrane interceptors and the TKIs. In terms of development status the most promising today are the TKIs.
We have been working on the enzyme FGFR3, from the moment when it is active there in the cell membrane. Is it possible to interfere with the production of FGFR3? In the next post we will visit the chondrocyte nucleus and search for opportunities where we could obstruct the mutant FGFR3 production. If the altered enzyme is not produced, it can’t cause bone growth arrest.

No comments:

Post a Comment