[Me: I have been in contact with Tyler of HeightQuest.Com for almost since the beginning and I have hoped that he could write a guest post for the website to speak about what he has found in his quest for height. Finally he managed to write something for all of us. This is his guest post. I have read it and I feel that this post is a very critical piece in understanding the genetics of growth and height. I wanted to thank Tyler again for his contributions.]
I have a done a lot of analysis on what genes are best for height growth. And there are several genes that are better targets than others.
Estrogen and it’s receptors are highly inefficient targets even though they are involved in height growth. Estrogen receptors have different effects based on differentiation stage and in gender. ERalpha, ERbeta, and GPR30 are the estrogen receptors typically identified with growth. And although GPR30 seems to be the most promising estrogen receptor height increase knockout targets, ERalpha and ERbeta have mixed effects in studies with knockout sometimes increasing and other times decreasing height. There are mutations with estrogen receptors in overgrowth but they are specific receptors.
p-ERK1 phosphorylation and formation of AP-1 complex is another gene target with mixed height increase results. Sometimes ERK1 phosphorylation stimulates chondrogenesis and other times it inhibits. Same with AP-1. Thus even though both ERK1 and AP-1 are important to height growth the conflicting results makes them poor targets.
GH is another poor target. Although IGF-1 is a good target for height growth, based on transgenic models of IGF-1 showing overgrowth, and it is downstream target of GH, GH is a poor target to try to increase via supplements or other methods to induce overexpression. Several HGH studies have shown no overgrowth and other GH related proteins like Ghrelin and GHRP showed no overgrowth when overexpressed. SOCS2 which is a GH inhibitor causes overgrowth when inhibited and we know GH is important to height growth. However, there are likely negative feedback mechanisms, likely SOCS2, that make GH overexpression not cause overgrowth. There are several studies that associate GH with Gigantism however most of those studies are based purely on phenotype and do not fully quantify what’s going on in the body. The tumor in all likelihood is doing things other than causing GH overexpression.
IGF2 is a very promising height increase target. IGF2 transgenic species show overgrowth. Reduction of IGF2R which reduces free IGF2 causes overgrowth. A specific mutation in H19 which seems to reduce free IGF2 also increases height. PLAG1 which increases IGF2 levels also causes overgrowth. The target of IGF2 and IGF1 is increasing Akt. LSJL increases Akt phosphorylation according to Knee Loading Stimulates Bone Formation in Tail-Suspended Mouse Hindlimb. Loads in this study were 1N at 5Hz for 5min. Same was taken 5 days after initiation of LSJL. One day after loading. Akt1 and phosphorylation of Akt1 is also associated with overgrowth.
CNP is also uniformly associated with height increase. Knockout of the CNP inhibitor FGFR3 increases height. Knockout of the CNP decoy receptor NPR3 and upregulation of the CNP actual receptor NPR2 also increases height. CNP and it’s regulators are very promising targets for height increase.
The SHOX genes are another great target with knockout causing short stature and transgenic overexpression causing tall stature.
HMGA2 and it’s regulators are another strong series of genes associated with overgrowth. LSJL upregulates several genes including HMGA2 and Lin28b which downregulates the HMGA2 inhibitor let-7.
Note that these targets will only work with active growth plates. The most likely reason that you can grow taller with chondrocytes and not osteogenic cells is that cartilage can grow interstitially(growth from within) wheres osteogenic cells typically don’t. Thus you need to induce chondrogenesis in the bone to grow taller if you don’t have active plates(LSJL upregulates the three major chondroinductive genes at significant levels Sox9, Aggrecan, and COL2A1). There are several cases of non-invasive/non-tumor ectopic chondrogenesis in the bone but many seem to be in children and I haven’t found any associated with overgrowth. Too bad scientists won’t just induce ectopic chondrogenesis in an adult animal bone to see if it makes the bone grow longer.
But why are you focused on Estrogen and HGH when SOCS2, IGF2, SHOX, CNP, and HMGA2 are much better targets. HGH is a much less harmful target as overexpression has never caused reduced growth. However, knockout of estrogen and receptors have caused reduced growth which makes it a poor target for reduction with aromatase inhibitors. Other genes have much more linear effects and are much better targets.
MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature.
“We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways and fundamental cellular processes, followed by chromosomal aberrations including copy number variants and imprinting disorders associated with short stature. Many novel causes of growth hormone (GH) deficiency as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GH deficiency are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3 and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in approximately 3% of short children, and also rasopathies (e.g. Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, copy number variants and imprinting disorders.”
“IGF-II not only is a mediator of intrauterine development but also contributes to postnatal growth “