Saturday, June 23, 2012

Build your Stature by Inhibiting FGF-21?

We know that the periosteum expresses FGF-21.  The periosteum likely plays a key role in height growth.  Here's a study that directly links FGF-21 inhibiting the growth plate:

Fibroblast Growth Factor 21 (FGF21) inhibits chondrocyte function and Growth Hormone (GH) action directly at the growth plate.

"Fibroblast Growth Factor 21 (FGF21) modulates glucose and lipid metabolism during fasting. In addition, previous evidence indicates that increased expression of FGF21 during chronic food restriction is associated with reduced bone growth and Growth Hormone (GH) insensitivity. In light of the inhibitory effects on growth plate chondrogenesis mediated by other FGFs, we hypothesized that FGF21 causes growth inhibition by acting directly at the long bones' growth plate. We first demonstrated the expression of FGF21, FGFR1 and FGFR3 (two receptors known to be activated by FGF21)[we know that FGFR3 is very bad for height growth and can cause dwarfism], and β-klotho (a co-receptor required for the FGF21-mediated receptor binding and activation) in fetal and 3-week old mouse growth plate chondrocytes. We then cultured mouse growth plate chondrocytes in the presence of graded concentrations of rhFGF21 (0.01-10 μg/ml). Higher concentrations of FGF21 (5 and 10 μg/ml) inhibited chondrocyte thymidine incorporation and collagen X mRNA expression. 10 ng/ml GH stimulated chondrocyte thymidine incorporation and collagen X mRNA expression, with both effects being prevented by the addition in the culture medium of FGF21 in a concentration-dependent manner[So chondrocyte thymidine incorporation and collagen X expression might result in more height growth, we know that collagen X expression is a factor in chondrocyte hypertrophy]. In addition, FGF21 reduced GH binding in cultured chondrocytes. In cells transfected with FGFR1 siRNA or ERK 1 siRNA, the antagonistic effects of FGF21 on GH action were all prevented, supporting a specific effect of this growth factor in chondrocytes[So the negative effects of FGF21 on GH action are a result of the increased ERK1 phosphorylation and FGFR1]. Our findings suggest that increased expression of FGF21 during food restriction causes growth attenuation by antagonizing the GH stimulatory effects on chondrogenesis directly at the growth plate. In addition, high concentrations of FGF21 may directly suppress growth plate chondrocyte proliferation and differentiation."

"transgenic mice overexpressing FGF21 are significantly smaller, have reduced tibial length, and display reduced hepatic GH insensitivity when compared to wild-type mice"

FGF21 also increases ERK 1 phosphorylation.

So to grow taller we can either find ways to directly inhibit FGF21 or inhibit FGFR3 and FGFR1.  We already know that CNP inhibits FGFR3.

Lactose may enhance FGF21 signaling:

Dynamics and Distribution of Klothoβ (KLB) and Fibroblast Growth Factor Receptor-1 (FGFR1) in Living Cells Reveal the Fibroblast Growth Factor-21 (FGF21)-induced Receptor Complex.

"FGF21 stimulates FGFR1c activity in cells that co-express Klothoβ (KLB); however, relatively little is known about the interaction of these receptors at the plasma membrane. We measured the dynamics and distribution of fluorescent protein-tagged KLB and FGFR1c in living cells using fluorescence recovery after photobleaching and number and brightness analysis. We confirmed that fluorescent protein-tagged KLB translocates to the plasma membrane and is active when co-expressed with FGFR1c. FGF21-induced signaling was enhanced in cells treated with lactose, a competitive inhibitor of the galectin lattice, suggesting that lattice-binding modulates KLB and/or FGFR1c activity. Fluorescence recovery after photobleaching analysis consistently revealed that lactose treatment increased KLB mobility at the plasma membrane, but did not affect the mobility of FGFR1c. The association of endogenous KLB with the galectin lattice was also confirmed by co-immunoprecipitation with galectin-3. KLB mobility increased when co-expressed with FGFR1c, suggesting that the two receptors form a heterocomplex independent of the galectin lattice. Number and brightness analysis revealed that KLB and FGFR1c behave as monomers and dimers at the plasma membrane, respectively. Co-expression resulted in monomeric expression of KLB and FGFR1c consistent with formation of a 1:1 heterocomplex. Subsequent addition of FGF21 induced FGFR1 dimerization without changing KLB aggregate size, suggesting formation of a 1:2 KLB-FGFR1c signaling complex. Overall, these data suggest that KLB and FGFR1 form a 1:1 heterocomplex independent of the galectin lattice that transitions to a 1:2 complex upon the addition of FGF21."

Now milk and diary have a lot of beneficial effects on height growth.  Maybe lactose free milk will give the benefits of milk without inhibiting galectin lattice.  Lactoferrin can also be taken directly.

There are prescription FGFR inhibitor drugs but you only want to inhibit FGFR1 and FGFR3 not FGFR2 and FGFR4.

Bone Marrow Mesenchymal Stem Cells: Fat On and Blast Off by FGF21.

"activation of the Wnt/β-catenin signaling pathway can stimulate BMMSCs to differentiate into osteoblast but inhibit adipogenesis and chondrogenesis"

"[fgf21] is a powerful regulator of glucose and lipid metabolism. Physiologically, FGF21 expression is induced both in the liver by prolonged fasting via PPARα activation and in the white adipose tissue by feeding via PPARγ activation. Pharmacologically, administration of recombinant FGF21 to diabetic mice and rhesus monkeys strongly enhances insulin sensitivity, [and] decreases plasma glucose and triglyceride"

"genetic loss-of-function as in the FGF21 knockout mice leads to a higher bone mass with less marrow adipocytes but more osteoblasts and accelerated bone formation."

"FGF21 forms a feed-forward loop with PPARγ: ligand activation of PPARγ increases the expression of FGF21 and its co-receptor β-Klotho in BMMSCs; in turn, FGF21 enhances PPARγ activity by attenuating its inhibitory sumoylation"


  1. are there any more FGF receptors that are inhibitory to growth or is that all of them?

    anyway, this sounds very promising.

  2. hi, wanted to make a recommendation, can you look into cortisol levels and height? is it beneficial to increase them or to keep them lower?

  3. Hey Tyler!

    Could you possibly make a blog about the importance of sleep? Or at least a study of sorts?

    I know it's common sense that growth happens during sleep, but it would be nice to know the chemical changes that happen during so.

    Not only that, but your wonderfully eclectic archive is lacking a sleep article and we have to make sure you cover everything :D