The Link Between FGFR3 and CNP Expression – Raja’s Research Summarized

Ever since the a commenter who calls himself Raja has shown me the study of the link between FGFR3 and Achondroplasia and I realized that it might be one of the easier, most promising ways that real companies have been doing to try to help at least children increase in height, I realized that I should take a more serious look at what this researcher had to say. So I asked him/her about the research they have been doing. Here is our exchange of emails.

Me —> D Inventor

Your response to one of my posts have been very interesting. I plan to write a detailed post about the study and see where it will take the research.

I have done mostly studies on fgf2 and basic fgf2, nothing on fgf 3 yet.

So can you show me the research you have been doing?
and how comfortable do you feel about coming on the podcast and explain your own research?

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What I’ve found so far.

Children: To the best of our knowledge there is currently only one company worldwide, that researches an innovative height increase therapy: ProChon Biotech (http://www.prochon.com), established in  Israel in 1997. ProChon is developing a monoclonal antibody for the treatment of achondroplasia. This antibody approach targets specifially the FGFR3-gene and hasn´t reached the stage of human clinical trials yet. If it is successful, it will only work for children with achondroplasia. – http://www.makemetaller.org/index.php/topic,578.0.html

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D Inventor —> Me

I’ll give you a summary of what I’m working on.

Basically, our bodies are designed to only grow to a certain extent – this is really why our height is determined by our genes. Growing taller than our “predetermined” height is called skeletal overgrowth. When I started researching, I found an article on CNP in which scientists increased substantially the plasma concentration of CNP, which resulted in skeletal overgrowth of the mice models (1, 2). You can really just google this for more info, but I’ve provided the links at the end of this message. I read another article which found a family with genetic mutation that caused an overexpression of the NPPC gene, which controls the expression and production of CNP (3). Basically, everyone in this family was really tall.

Another interesting article was on FGFR3 knockout, which lead to skeletal overgrowth in mice models (4). CNP works as an antagonist to FGFR3, which is evident as CNP is able to rescue achondroplasia models with constitutive FGFR3 activation.

Here’s how CNP works (just some technical information, but this is important for when we get into the pharmaceuticals specifications):

– CNP activates its receptor GC-B, which releases cGKII (5)
– cGKII works by inhibiting the conversion of Ras into Raf (look up FGFR3 phosphorylation)
– This acts as a inhibitor to the activation of the MAPK cascade. This is important to endochondral ossification as it inhibits ERK1/2 phosphorylation.

Essentially, one way that CNP exerts its bone promoting effects is through the inhibition of ERK1/2 activation (one of two pathways that are activated with FGFR3). You can really just search up “ERK1/2 inhibition” on google and see that other scientists have achieved skeletal overgrowth in mice models in which they inhibited ERK1/2.

OKAY, enough with background info. If I’m rabbling, I apologize. It’s just that there really is a lot of information on this.

Back to FGFR3 – its inhibition leads to skeletal overgrowth and it WILL increase a person’s final height. Many people with mutations that diminish FGFR3 expression have really tall stature.

So, for us, people who want to be taller, the easiest way for us to get taller is to inhibit FGFR3. The article I posted on your website discusses how there was an increase in the height of the growth plate in a person whose growth plate was about to close (or was in fact closed). This is interesting because in the article, the individual’s growth plate was reduced to a growth scar. This usually happens when the growth plate is just about to close. However, if used in conjuction with LSLJ (if this method really does cause microfractures), then it MIGHT be effective for people with closed growth plates, since it MIGHT just help regrow growth “plates” on a micro scale, and could possibly lead to a few more inches.

So, back to FGFR3 inhibition. As far as I’ve researched, this seems to be an effective method for people with open growth plates. The problem with current FGFR3 tyrosine kinase inhibitors is the lack of specificity. But, I’ve found a novel drug which seems very specific to the FGFR family, called AZD 4547. So far, at least in vitro studies, it is by far the most selective that I’ve found, towards FGFR3. The benefit of chemical inhibitors is that they target everywhere in the body, so that growth is proportional.

While I can’t really advise anyone to take this compound, I’m trying to find a synthesis method for this compound.

If you need any more info, feel free to ask.

References:

1. Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice, Source: http://ajpendo.physiology.org/content/297/6/E1339.full.pdf

2. C-type natriuretic peptide and overgrowth. , Source: http://www.ncbi.nlm.nih.gov/pubmed/19293575

3. An Overgrowth Disorder Associated with Excessive Production of cGMP Due to a Gain-of-Function Mutation of the Natriuretic Peptide Receptor 2 Gene, Source: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0042180

4. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. , Source: http://www.ncbi.nlm.nih.gov/pubmed/8630492

*Just a note, while it says it causes deafness, this on a genetic knockout study. Deafness is caused by a developmental defect when the mice are embryos or just as they are growing. In humans (that are mature and fully developed), with inhibition of FGFR3, there should not be any problems with deafness (to the best of my knowledge).

5. Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification. – Source: http://www.ncbi.nlm.nih.gov/pubmed/12193576

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My Response to D Inventor

Tyler noted the link between FGFR3 and CNP as well as the link between FGFR3 and ERK 1 & 2. I  have absolutely no research on ERK 1&2 and don’t even know what they are yet. I can not comment or make any good judgement on how ERK affects everything.

I’ve done the research on CNP before and the research was done by many other height increase researchers in the past from the GrowTallForum.com which is now closed. They tried to increase their height through finding compounds that could increase the level of CNP or Nitric Oxide in their systems. I found at least one patent by some Japanese guy who showed that increased CNP would help children who are suffering from idiopathic short stature.

It is very clear that there is a chance that increased CNP levels in the blood would negate the function of FGFR3 to a certain level in humans suffering from Achondroplasia. Refer to the post CNP, the first potential pharmacological therapy for achondroplasia

From that post, it states “Biomarin, a pharmaceutical company working in therapies for rare and genetic conditions, announced it was planning to start the clinical research with a compound called BMN-111. BMN-111 was described as a C-type Natriuretic Peptide (CNP) analogue.

So from this article, it shows that there is still a lot of options and hope for kids who are still growing . CNP does not have to be the only option.

I read over the article you referenced quite extensively entitled “Cartilage Dysplasia and Tissue Mineralization in the Rat Following Administration of a FGF Receptor Tyrosine Kinase Inhibitor”

I wanted to first make the point that the study was done on lab rats, not humans. It might not even be able to be translated to humans. The reason for this is like I said before, mature rats still have growth plate cartilage.

In the paper, the mature mice were defined to be around 11 months old. I googled the term “at what age do rats stop growing”. The information is mixed but the general answer is that they usually stop growing around the 8-10 month range. Refer to RatForum.com. So technically the “mature” rats in the experiment should have stopped growing in bone length.

The paper does say that the cartilage in the mature rats did go through hyperplasia. However, the main point and problem I would bring up is that unlike humans, even mature and old rats (and possible mice) still have bands of cartilage in their limbs. The long bones of old rats are not completely bone, but have portions that are stil cartilage. Humans don’t have that physiology. Our limbs become all bone except at the ends.

Remember that most of the people who ever ask about how to grow taller already have their plates fused. They are already in a very difficult position when they start to ask for help and look for solutions.

What happens usually is that while a person is still young and have open plates, even if they are short they still rationalize in their mind and hope that they just haven’t gotten the chance to go through their growth spurts yet, even if they never will get one. Everyone hopes that they would be one of the lucky ones who gets to go through a 6-7 inch growth spurt and that would happen to them. For most people, that doesn’t happen. So they wait and don’t do much except wish and hope, and they run out of time when the cartilage is all gone. After they notice that they are still short even after puberty, then they start worrying since they never got the growth spurt that they ‘deserved’ or expected to get and start to search. It is already too late.

Me and the other researchers have found multiple ways for children with open growth plates get taller. That is easy. Finding a way for fused cartilage has been the problem, and will always be the problem. That is the real solution we want to find.

What we always focused on was a solution for people with bone maturity, because we all understand that ultimately, that is the real solution.

 

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