Growing Taller with IGF-1?

IGF-1 promotes growth in every cell in the body and encourages cell growth and development. My hypothesis is that IGF-1 will promote growth in the periosteum of irregular, short, and flat bones resulting in the Tito Ortiz or Kurtwood Smith head but not in the long bones as the limiting factor is mesenchymal(red bone marrow) stem cells and if they are not already in the growth plate they will cannot replicate(multiplying 0 by 100 is still zero). If you are pre-puberty, then injecting your mesenchymal stem cells with IGF-1 may result in a greater "final" adult height.  IGF-1 has systematic affects as well so if you manage to increase your system IGF-1 levels while getting around the negative feedback induced reduction of insulin sensitivity you will be taller.  The best place for the IGF-1 is probably the somotrophic portion of the anterior pituitary which regulates growth and has been linked with gigantism.

High serum levels of IGF-I contribute to promotion of endochondral ossification in mandibular condyle and cause its specific elongation in acromegaly-like rats.

"Mandibular protrusion accompanies acromegaly or acrogigantism. To clarify the detailed mechanisms, we used an acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I). Human recombinant IGF-I (640 microg/day) continuously was infused subcutaneously to 10-week-old male rats (n=12) for four weeks[Ten week old rates are not very old]. Control, sham-operated animals (n=12) were injected with saline alone. Twelve rats (six from each group) were killed immediately after ending administration at age 14 weeks. Another 12 rats (six from each group) were housed for an additional four weeks after treatment ended. Mandibular condylar length increased significantly in the IGF-I rats compared with the control rats, but no significant intergroup difference was found in the lengths of the coronoid and angular processes. Cartilaginous layer width, bone matrix volume, and the number of osteoblasts in the mandibular condyle increased significantly in the IGF-I group. These histopathological changes in the condyle disappeared after IGF-I administration was discontinued; however, the morphological change in condylar length remained. These findings suggest that mandibular protrusion in patients with acromegaly or acrogigantism may be evoked by superfluous elongation of the mandibular condyle and that such elongation can be induced by endochondral ossification caused by high IGF-I serum levels."

Endochondral ossification is the process involved in long bone growth. Since the IGF-1 was applied systemically thus suggests that increasing IGF-1 levels may increase final height. Here's a picture of the mandible:




One explanation for why only the mandibular condyle grew is that the mandibular condyle is the part of the jaw bone that is most like a long bone. It states that there was no significant increase in length in the other areas perhaps there was an insignificant increase in periosteal width.

Growth Hormone, Insulin-Like Growth Factors, and the Skeleton

According to the article, IGF-1 operates independently of GH in embryonic development. Both IGF-1 and GH have an effect on periosteal width post puberty, to see the power of periosteal width in action just look at Andre the Giant... IGF-1 has both systematic and local effects.

"GH affects the fate of mesenchymal precursors favoring osteoblastogenesis and chondrogenesis and opposing adipogenesis. Mesenchymal precursor cells can differentiate into adipocytes, osteoblasts, and chondrocytes in a tightly controlled process."

GH encourages mesenchynal stem cells to turn into osteoblasts or cartilage rather than adipose tissue.





The less bold of a line, the less of an effect one factor has on another. Of course, mesenchymal stem cells should also be pointing to the growth plate as well.

"Transgenic mice overexpressing IGF-I under the control of the osteoblast-specific osteocalcin promoter exhibit transient increases in trabecular bone secondary to an increase in osteoblast function and bone formation. Changes in osteoblast number were not observed, confirming the predominant effect of IGF-I on osteoblastic function, and not on mitogenesis."

Mitogenesis of course being the money maker, cell proliferation and within the grown plate: height gain.

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat
 
"GH treatment of children with idiopathic short stature or SGA(low birth weight?) does not lead to achievement of genetic height potential"

"The present trial utilized acipimox acts as an antilipolytic agent. Acipimox can lower plasma insulin concentrations and has been shown to enhance spontaneous GH secretion in obese humans and to considerably enhance GH secretion in response to various secretagogues. Acipimox has also been shown to restore the GH response to GH-releasing hormone in elderly subjects."

"GH increased tibial length in all treated groups relative to saline-treated controls."  Including the normal sized rat group.

"GH plus acipimox treatment further significantly enhanced the GH-induced effects on tibial growth."

"Plasma IGF-I concentrations were increased in GH and GH-plus-acipimox-treated control."

So the increase in tibial bone length could be a result in an increase in IGF-1 levels.

"Acipimox may have altered GH output through neural pathways via altered activation of dopaminergic neural circuits."

To those who want to induce gigantism but don't know how to get around the negative feedback mechanisms:

"Pharmacological antilipolysis can restore insulin sensitivity during growth hormone exposure."

IGF-1 has been shown to enhance somatic tissue growth(somatic being any body cell). This also means that you can grow taller by increasing your skin thickness or your cartilage thickness.

We know that exercise increases insulin sensitivity. Therefore, any form of exercise can make you taller by enhancing the effects of IGF-1 on your cells(but not significantly).  IGF-1 does seem to promote chondrogenic differentiation of stem cells.

Differential regulation of immature articular cartilage compressive moduli and Poisson's ratios by in vitro stimulation with IGF-1 and TGF-beta1.

"This study tested the hypothesis that IGF-1 and TGF-beta1 regulate immature cartilage compressive moduli and Poisson's ratios in a manner consistent with known effects on tensile properties[changes in cartilage shape, which are measured by compressive moduli and Poisson's ratio, alter hydrostatic pressure therefore IGF-1 and TGF-Beta1 alter hydrostatic pressure because they alter the effects of compression and tension]. Bovine calf articular cartilage from superficial-articular (S) and middle-growth (M) regions were analyzed fresh or following culture in medium with IGF-1 or TGF-beta1. Mechanical properties in confined (CC) and unconfined (UCC) compression, cartilage matrix composition, and explant size were assessed. Culture with IGF-1 resulted in softening in CC and UCC, increased Poisson's ratios, substantially increased tissue volume, and accumulation of glycosaminoglycan (GAG) and collagen (COL)[the three latter benefits definitely are beneficial for height growth]. Culture with TGF-beta1 promoted maturational changes in the S layer, including stiffening in CC and UCC and increased concentrations of GAG, COL, and pyridinoline crosslinks (PYR), but little growth[note though that this is existing articular cartilage and that TGF-Beta1 may have a larger effect on stem cells that have yet to differentiate into chondrocytes]. Culture of M layer explants with TGF-beta1 was nearly homeostatic. Across treatment groups, compressive moduli in CC and UCC were positively related to GAG, COL, and PYR concentrations, while Poisson's ratios were negatively related to concentrations of these matrix components[compressive moduli is essentially the resistance to compression.  A higher compressive moduli means a substance is more resistance to compression.  It's likely that GAG, COL, and PYR concentrations are causing the compression resistance.  When a material is compressed it stretches the material in the directions not being compressed.  So LSJL stretches the rest of the bone.  Poisson's ratio measures how much a material expands relative to how much it is compressed.  As material stretches more than it compresses, poisson's ratio gets higher.  GAG, COL, and PYR concentrations lowered Poisson's ratio but it also lowered compression therefore GAG, COL, and PYR concentrations must also resist bone stretching in all directions]. Thus, IGF-1 and TGF-beta1 differentially regulate the compressive mechanical properties and size of immature articular cartilage in vitro."

" Culture with IGF-1 is distinguished by significant tissue expansion at the expense of reduced tensile stiffness and strength. In contrast, culture with TGF-β1 maintains size and tensile properties"<-So both IGF-1 and TGF-B1 are likely needed for optimal height growth.  BMP-2 likely belongs somewhere in there too.

"dimensional changes in the 1- and 2-directions were small, averaging <5% for IGF-1 samples and <2% for TGF-β1 samples (data not shown), indicating that IGF-1 induced expansion primarily in the 3-direction." 50ng/ml of recombinant IGF-1 was used and 10ng/ml of recombinant TGF-Beta1 was used. 1-direction refers to left and right expension so width.  Direction-2 refers to up and down expansion so both IGF-1 and TGF-Beta1 would increase height by less than 5% and 2% respectively.  3-direction refers to front and back which won't really help for height growth but it does indicate that if you are increasing IGF-1 and TGF-Beta1 you should be seeing a significant increase in front and back thickness.  If you are not increasing front and back thickness you may not be increasing IGF-1 and TGF-Beta1 in a significant way.

Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling.

"IGF-I modulated MSC chondrogenesis by stimulating proliferation, regulating cell apoptosis, and inducing expression of chondrocyte markers. IGF-I chondroinductive actions were equally potent to TGF-beta1, and the two growth factors had additive effects. Using RIIKO-MSCs, we showed that IGF-I chondrogenic actions are independent from the TGF-beta signaling.  Extracellular signal-related kinase 1/2 mitogen-activated protein kinase (Erk1/2 MAPK) pathway mediated the TGF-beta1 mitogenic response and in part the IGF-I proliferative action."

"it is possible that the lack of IGF biological activity was caused by the nonspecific stimulation of IGFIR by the high levels of insulin present in the ITS Premix. In our study, we evaluated the IGF effects in the absence of insulin."<-So maybe you need low levels of insulin and high levels of IGF-1 to grow taller?

"IGF-I determined an increase in the expression of type II collagen and Sox-9 that was comparable with TGF-β1. "

IGF-1 can inhibit Wnt3A via IGFBP-4 thus reducing Beta-Catening stabliization and allowing for chondrogenesis.

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis.

"Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). Some of the actions of IGFBPs have been reported to be independent of IGFs. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling."

IGF-1 regulation of type II collagen and MMP-13 expression in rat endplate chondrocytes via distinct signaling pathways.

"Cultured endplate chondrocytes harvested from rat cervical spines were treated with IGF-1 (100ng/ml). Cells were also treated with pharmacological agents that block PI3K and MAPK signaling pathways.
IGF-1 increased Col2a1 mRNA expression in rat endplate chondrocytes in a time- and dose-dependent manner. IGF-1 treatment resulted in a fourfold increase of Col2a1 mRNA with the effect maximizing at 24h. In contrast, IGF-1 treatment for 24h caused a roughly 50% reduction in MMP-13 mRNA. Similar effects were seen on the protein levels of type II collagen (col2) and MMP-13. Consistent with these results, IGF-1 also repressed MMP-13 activity. IGF-1 activated both the PI3K and the extracellular signal-regulated kinase (ERK) pathways as evidenced by phosphorylation of either Akt or ERK1/2 (respectively){LSJL phosphorylates Akt}. The PI3K inhibitor Wartmannin significantly inhibited the IGF-1 effect on Col2a1 mRNA expression but did not affect IGF-1-induced repression of MMP-13 expression{LSJL stimulates the PI3K pathway}. In contrast, the ERK/MAPK inhibitor PD98059 significantly inhibited the effect of IGF-1 on MMP-13 mRNA repression and enhanced IGF-1-induced Col2a1 mRNA expression.
In rat endplate chondrocytes the PI3K pathway mainly transduces IGF-1 effect on col2 expression while the ERK pathway mediates IGF-1 effect on MMP-13 expression."

"IGF-1 exerts its biological effect by binding to the transmembrane type 1 IGF receptor and activating insulin receptor substrate-1"

IGF-1 had a linear effect on chondrocyte anabolism until at least 100ng/ml.

Insulin-like growth factor-I signaling is modified during chondrocyte differentiation.

"IGF-I has been shown to be a potent chondrocyte mitogen in vitro. We chose to study the action of IGF-I on an accepted model of chondrocyte differentiation, the ATDC5 cell line. Insulin concentrations sufficiently high to interact with the IGF-I receptor are routinely used to induce ATDC5 cells to differentiate. Therefore, we first examined the ability of IGF-I to promote chondrocyte differentiation at physiological concentrations. IGF-I could induce differentiation of these cells at concentrations below 10 nM. However, increasing IGF-I concentrations were less potent at inducing differentiation. We hypothesized that mitogenic effects of IGF-I might inhibit its differentiating effects. Indeed, the extracellular-signal-regulated kinase (ERK)-pathway inhibitor PD98059 inhibited ATDC5 cell DNA synthesis while enhancing differentiation. This suggested that the ability of IGF-I to promote both proliferation and differentiation might require that its signaling be modulated through the differentiation process. We therefore compared IGF-I-mediated ERK activation in proliferating and hypertrophic chondrocytes. IGF-I potently induced ERK activation in proliferating cells, but minimal ERK response was seen in hypertrophic cells. In contrast, IGF-I-mediated Akt activation was unchanged by differentiation, indicating intact upstream IGF-I receptor signaling. Similar findings were observed in the RCJ3.1C5.18 chondrogenic cell line and in primary chick chondrocytes. We conclude that IGF-I promotes both proliferation and differentiation of chondrocytes and that the differentiation effects of IGF-I may require uncoupling of signaling to the ERK pathway."

"GH receptor-null mice show severe postnatal growth retardation and extremely low circulating IGF-I levels. The growth plate in these animals narrows relative to wild-type animals starting at 2 weeks of age"

"Studies on ATDC5 cells have routinely employed the addition of high concentrations of insulin (10 μg/ml) to induce chondrocyte differentiation. "

Cartilage disorders: potential therapeutic use of mesenchymal stem cells.

"Insulin-like growth factors (IGFs) play a central role in chondrogenesis as indicated by the severe growth failure observed in animals carrying null mutations of Igfs and Igf1R genes. We have found that IGF-I has potent chondrogenic effects in MSC. Effects are similar to transforming growth factor-Beta (TGF-Beta). Insulin-like growth factor binding protein-3 (IGFBP-3), well characterized as IGF carrier, has intrinsic bioactivities that are independent of IGF binding. IGFBP-3 levels are increased in degenerative cartilage diseases such as osteoarthritis. IGFBP-3 has IGF-independent growth inhibitory effects in chondroprogenitors. IGFBP-3 induces MSC apoptosis and antagonizes TGF-Beta chondroinductive effects in chondroprogenitors."

Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice

So osteocyte signaling can affect endochondral ossification so the diaphysis effects of LSJL may be relevant to the epiphyseal lengthening effects.

"osteocyte Igf1 conditional knockout (KO) mice [were] generated by crossing the Dmp1-driven Cre-expressing transgenic mice with Igf1 floxed mice containing loxP sites that flank exon 4 of the Igf1 gene. The periosteal diameter of femurs of homozygous conditional KO mutants was 8–12% smaller than wild-type (WT) littermates. The conditional mutants had 14–20%, 10–21%, and 15–31% reduction in total, trabecular, and cortical bone mineral contents, respectively. However, there were no differences in the total, trabecular, or cortical bone mineral densities, or in trabecular bone volume, thickness, number, and separation at secondary spongiosa between the mutants and WT littermates. The conditional KO mutants showed reduction in dynamic bone formation parameters at both periosteal and endosteal surfaces at the mid-diaphysis and in trabecular bone formation rate and resorption parameters at secondary spongiosa. The lower plasma levels of PINP and CTx in conditional KO mice support a regulatory role of osteocyte-derived IGF-1 in the bone turnover. The femur length of conditional KO mutants was 4–7% shorter due to significant reduction in the length of growth plate and hypertropic zone. The effect on periosteal expansion appeared to be bigger than that on longitudinal bone growth. The conditional KO mice had 14% thinner calvaria than WT littermates, suggesting that deficient osteocyte IGF-1 production also impairs developmental growth of intramembraneous bone. Conditional disruption of Igf1 in osteocytes did not alter plasma levels of IGF-1, calcium, or phosphorus[so it must be a direct signaling effect by osteocytes affecting longitudinal growth and not just a general effect due to elevated plasma]."

"Osteocytes are derived from osteoblasts as they become terminally differentiated and fully entrapped by the bone matrix."

"osteocytes regulate bone homeostasis by releasing paracrine factors, such as sclerostin, RANKL (receptor activator of nuclear factor kappa-β ligand) and produce and secrete fibroblast growth factor 23 (FGF23)."

"osteoblasts and osteocytes synthesize and release into circulation of under-carboxylated osteocalcin"

"osteocytes express large quantities of IGF-1 [and is upregulated in response to mechanical loading]" Not observed in LSJL however.

"the disruption of hepatic[liver] IGF-1 showed no significant impact on bone growth at early life, despite the fact that it decreased circulating IGF-1 levels by more than 75%".  Disruption of the igf1 gene resulted in shorter bones.

"the body and bone growth in the mutants with Igf1 conditional deletion in type 1α2 collagen-expressing osteoblasts were blunted at as early as 2 weeks of age, whereas the conditional ablation of Igf1 from type 2α1 collagen-expressing chondrocytes did not significantly suppress growth until the animals were at 8 weeks of age"

"Despite the substantial reduction in the Igf1 mRNA expression in osteocytes, the plasma IGF-1 level of KO mutant mice was not different significantly from that of WT littermates. However, the mutant mice showed significantly elevated levels of IGFBP3 but reduced levels of IGFBP5 at both 4- and 16-weeks of age,"

Bone length in IGF-1 KO mice was decreased by about 10%.

"The bone of osteocyte Igf1 conditional KO mice appears to be insensitive to loading, it is possible that the blunted longitudinal bone growth was a consequence of the decreased bone mechanosensitivity in osteocyte Igf1 conditional KO mutants."

Treatment of growth plate injury using IGF-I-loaded PLGA scaffolds.

"[We] develop an in vivo tissue-engineering approach for the treatment of growth plate injury via localized delivery of insulin-like growth factor I (IGF-I) from cell-free poly(lactic-co-glycolic acid) (PLGA) scaffolds. Mass loss and drug release studies were conducted to study the scaffold degradation and IGF-I release patterns. Rat bone marrow stromal cells seeded on the porous scaffolds colonized the pores and deposited matrix within the scaffolds. Implantation of scaffolds in proximal tibial growth plate defects in New Zealand white rabbits showed regeneration of cartilage, albeit with disorganized structure, at the site of implantation of IGF-I-releasing scaffolds; in contrast, only bone was formed in empty defects and those treated with IGF-free scaffolds."

Treatment with insulin-like growth factor-1 increases chondrogenesis by periosteum in vitro.

"Gene expression by periosteal explants in vitro was measured. Expression of type II collagen and aggrecan mRNA was increased in response to treatment with IGF-I. IGF-I treatment caused an increase in type II collagen and aggrecan mRNA that was time and concentration dependent. The effect of short and long-term (continuous) incubations was compared to determine if a pretreatment could be used to condition a graft for subsequent surgical use. Short-term incubation in vitro with IGF-I followed by incubation without IGF-I was nearly as effective at increasing expression of type II collagen and aggrecan mRNA as incubation for the same length of time with IGF-I present continuously in the culture media {So there may be a negative feedback mechanism or conditioning effect}. Treatment with IGF-I also produced cell clustering and nodule formation which are indicative of chondrogenesis{Which is also indicative of new growth plate formation}."

"fibrocartilage [degenerates] upon mechanical loading"

"Periosteum consists of two distinct layers, an outer fibrous layer and a more cellular cambium layer. Cells from the cambium layer are osteochondral and participate in the cartilaginous phase of fracture healing. During this phase, cells express aggrecan, type II collagen and type X collagen"  IGF-1 did not upregulated type I collagen.

"it may be possible to elicit chondrogenesis in vivo by treating periosteal grafts for short periods immediately prior to implantation."

Anabolic effects of IGF-1 signaling on the skeleton.

"GH promotes the formation of a ternary IGF binding complex composed of the acid-labile subunit (ALS) and IGF binding protein 3 (IGFBP-3), which in turn act to stabilize serum IGF-1."

"insulin receptor substrate (IRS) family [associates] with IGF-1R via PTB and SH2 domains, growth receptor binding protein-2 (Grb2) binds to specific motifs in the IGF-1 receptor as well as in IRS, and the p85 subunit of phosphatidyl inositol-3 kinase (PI3K) binds to other specific motifs within IRS. Shc, when tyrosine phosphorylated in response to IGF-1, binds to the SH2 domain of Grb2, which in turn forms a complex with Sos, a guanine nucleotide exchange factor."

IGF-1/PI3K/AKT pathway can increase BLC2 reducing apoptosis and increase cyclin D1 increasing cell proliferation.

Osteocalcin specific Knockout of IGF-1R did not increase bone length.  Global IGF-1 knockout and DMP1(IGF-1KO), Col1a2(IGF-1KO), Col2a1(IGF-1&IGF-1R KO), and hepatic IGF-1 knockout all reduced bone length.

"Rasgrf1 null animals exhibit decreased postnatal skeletal growth, decreased serum IGF-1 levels and reduced IGF-1 transcripts in the liver."

A novel mutation in IGFALS, c.380T>C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinemia in two siblings: insights into the roles of insulin growth factor-1 (IGF1).

"The acid-labile subunit (ALS) protein is crucial for maintaining the circulating IGF/IGFBP system. Inactivating mutations of IGFALS result in IGF1 deficiency associated with growth retardation. Although the first IGFALS mutation in humans was described in 2004, only 16 mutations have been reported since. Moreover, the phenotype of affected patients as a consequence of ALS deficiency is still highly variable. We assessed whether children with idiopathic short stature (ISS) harbor mutations in IGFALS and characterized affected patients' phenotype.
Sixty-five children with ISS were enrolled in the study. Serum ALS levels were measured by ELISA and IGFALS was sequenced.
A novel homozygous mutation in IGFALS, c.380T>C (p.L127P), was identified in two siblings of a consanguineous family. The proband, a 17.75-year-old male, was -1.9 SDS in height and -4.5 SDS in weight. Exaggerated stimulated GH (38 ng/ml), and extremely low IGF1 and IGFBP3 (<25 ng/ml and <500 ng/ml, respectively) indicated GH insensitivity. Both affected siblings had low or no ALS (43 and 0 mU/ ml, respectively). They were also mildly small for gestational age, severely underweight, and showed osteopenia, insulin insensitivity and delayed and slow puberty progression.
ALS deficiency due to IGFALS mutations is a rare cause of growth retardation in children. The unique combination of features presented by the two affected siblings emphasizes the important role of IGF1 in bone formation, insulin regulation and the pubertal process, in addition to its crucial effect on growth."

"IGFALS, located on chromosome 16p13.3, encodes the protein acid-labile subunit (ALS) which forms a ternary complex with IGF1 and IGFBP3 and IGFBP5."

"The main role of ALS is to extend the half-life of IGF1 by protecting the ternary complex from degradation. Mutations in IGFALS result in low plasma ALS concentrations"

"Inactivation of IGFALS in mice results in a lack of ALS causing only modest growth failure."

Modeling the Insulin-Like Growth Factor System in Articular Cartilage.

"We estimate the degradation half-lives of free IGF-I and IGFBPs in normal cartilage to be 20 and 100 mins respectively, and conclude that regulation of the IGF half-life, either directly or indirectly via extracellular matrix IGF-BP protease concentrations, are two critical factors governing the IGF-IR complex formation in the cartilage. Further we find that cellular regulation of IGF-II production, the IGF-IIR concentration and its clearance rate, all significantly influence IGF signaling. It is likely that negative feedback processes via regulation of these factors tune IGF signaling within a tissue, which may help explain the recent failures of single target drug therapies aimed at modifying IGF signaling."


This diagram shows that stimulating the brain, kidney, and muscles may be a way to stimulate IGF-II.

"There is a certain threshold of IGF-I/ IGF-IR concentration that needs to be exceeded before protein synthesis is activated"