Basic helix-loop-helix transcription factor twist1 inhibits the transacivator function of the masterchondrogenic regulator Sox9.
"Canonical Wnt signaling strongly inhibits chondrogenesis[Thus for LSJL to work properly we must inhibit Wnt, people have alluded to this in previous comments]. Twist1 [is] a critical downstream mediator of Wnt in repression of chondrocyte differentiation. Twist1 suppresses cartilage development by directly inhibiting the transcriptional activity of Sox9[so inhibiting Twist1 may be more beneficial for chondroinduction than stimulating Sox9], the master regulator of chondrogenesis.Twist1, through its carboxyl-terminal Twist-box, binds to the Sox9 HMG DNA-binding domain, inhibiting Sox9 transactivation potential. In chondrocyte precursor cells, Twist1, in a Twist-box-dependent manner, inhibits Sox9-dependent activation of chondrocyte marker gene expression by blocking Sox9-enhancer DNA association. The balance between Twist1 andSox9 may determine the earliest steps of chondrogenesis."
Having a high bodyfat percentage may help decrease Twist1 levels:
[We] assess the expression of twist1 in human white adipose tissue (WAT), its relationship to obesity and insulin sensitivity, and how it modifies TNFα-mediated inflammation in adipocytes.
Twist mRNA levels were measured in WAT from 130 nonobese and obese subjects. Twist1 expression was measured before and after weight loss as well as in different adipose regions. Human in vitro differentiated adipocytes were treated with TNFα under control conditions or after twist1 gene silencing by RNA interference.
Twist1 expression was low in obese subjects and increased after weight loss. Twist1 mRNA levels correlated with adiponectin levels and inversely with insulin resistance as well as adipocyte volume[there's been evidence of insulin resistance for height increase before] (P < 0.001 for all). Low twist1 expression associated with a hypertrophic adipose tissue and high secretion of TNFα and monocyte chemoattractant protein-1 from WAT. Finally, twist1 silencing in human adipocytes enhanced TNFα-induced monocyte chemoattractant protein-1 expression and secretion, which was paralleled by an increase in the mRNA expression of the nuclear factor-κB gene RelA.
Low twist1 expression in human WAT correlates with obesity and an insulin-resistant phenotype, which may be mediated by an increased sensitivity to the proinflammatory effect of TNFα."
Although will reduced twist1 mRNA in adipose tissue reduce twist1 mRNA in bone tissue? Perhaps more twist1 mRNA in fat means less in the bone. Unfortunately, the scientists only measured twist1 mRNA in adipose tissue. Although the cause of low twist1 levels being insulin resistance may be the same in both bone and fat and why insulin resistance can result in increased height.
IGF-1 may too increase Twist1 levels.
"We investigated the molecular mechanisms whereby insulin-like growth factor 1 (IGF-1) induced Twist gene expression and the role of Twist in the anti-apoptotic actions of the IGF-1 receptor. In NIH-3T3 fibroblasts overexpressing the human IGF-1 receptor (NWTb3), treatment with IGF-1 (10(-8) m) for 1 and 4 h increased the level of Twist mRNA as well as protein by 3-fold. In contrast, insulin at physiological concentrations did not stimulate Twist expression in NIH-3T3 fibroblasts overexpressing the human insulin receptor. The IGF-1 effect was specific for the IGF-1 receptor since, in cells overexpressing a dominant negative IGF-1 receptor, IGF-1 failed to increase Twist expression. Pre-incubation with the ERK1/2 inhibitor U0126 or expression of a dominant negative MEK-1 abolished the effect of IGF-1 on Twist mRNA expression in NWTb3 cells, suggesting that Twist induction by IGF-1 occurs via the mitogen-activated protein kinase signaling pathway. In vivo, IGF-1 injection increased the mRNA level of Twist in mouse skeletal muscle, the major site of Twist expression. Using an antisense strategy, we demonstrated that a reduction of 40% in Twist expression decreased significantly the ability of IGF-1 to rescue NWTb3 cells from etoposide-induced apoptosis. Twist [is] an important factor involved in the anti-apoptotic actions of the IGF-1 receptor."
While Twist1 may be important for development, lowering Twist1 mRNA levels may result in enhanced growth plate driven height growth and more LSJL induced chondrogenesis. Ser68 may be a key target to lower Twist1 mRNA. Unfortunately, supplements that reduce Twist1 levels could not be found.
The study Persistent expression of Twist1 in chondrocytes causes growth plate abnormalities and dwarfism in mice found problems with both too high and too low levels of Twist1 this could be due to Sox9 levels needing to be at equilibrium.
Twist1 mediates repression of chondrogenesis by β-catenin to promote cranial bone progenitor specification.
The study Persistent expression of Twist1 in chondrocytes causes growth plate abnormalities and dwarfism in mice found problems with both too high and too low levels of Twist1 this could be due to Sox9 levels needing to be at equilibrium.
Twist1 mediates repression of chondrogenesis by β-catenin to promote cranial bone progenitor specification.
"The bones of the mammalian skull vault form through intramembranous ossification. Skull bones ossify directly, in a process regulated by β-catenin, instead of passing through a cartilage intermediate. removal of β-catenin from skull bone progenitors results in the near complete transformation of the skull bones to cartilage, whereas constitutive β-catenin activation inhibits skull bone fate selection. β-catenin directly activated Twist1 expression in skull progenitors, conditional Twist1 deletion partially phenocopied the absence of β-catenin, and Twist1 deletion partially restored bone formation in the presence of constitutive β-catenin activation. Twist1 bound robustly to the 3'UTR of Sox9, the central initiator of chondrogenesis. β-catenin signaling via Twist1 actively suppresses the formation of cartilage and promotes intramembranous ossification in the skull."
"Twist1 is required for the early migration and survival of cranial mesenchyme, which gives rise to the skull bones"
"Beta-catenin activates and functions through Twist1 to promote a bypass of chondrocyte fate (Sox9+)"
"deletion of Twist1 from mesenchymal progenitors of the appendicular skeleton does not result in the formation of ectopic chondrocytes"
"Sox9 overexpression is sufficient at high levels to inhibit bone formation in vivo"
Maybe LSJL isn't very effective on people with low body fat.
ReplyDeleteTwist1 is a downstream signalling pathway of WNT. Similar to AKT which is downstream of IGF-1. If you don't want AKT, you get rid of IGF-1. Similarly if you don't want twist1, you block the...
ReplyDeleteOne more thing you should note, Beta catenin is strongly involved with TWIST1.
So if we inhibit TWIST1, will we enhance our chondrogenesis by a lot? Will we grow much faster with LSJL?
ReplyDeletemaybe just find a way to upregulate sox9?
ReplyDeleteThere are ways to upregulate sox9, I already told you hundreds of times
ReplyDeletetgf-b increases sox9 levels while it also increases twist1. Since an increase in sox9 was seen, even when it also increased a sox9 DEcreasing gene you should stop wasting your time on this useless study
ReplyDeletei know you are leaving no stone unturned in the quest for height but if drug designers/makers havent successfully found a drug to inhibit twist 1 then what chance do we have ?
ReplyDeleteWell Twist1 inhibition may be important in fighting cancer so eventually there may be more ways to fight Twist1.
DeleteIt says it plain as day in the study:
ReplyDeleteCanonical Wnt signaling strongly inhibits chondrogenesis. Previously, we identified Twist1 as a critical downstream mediator of Wnt in repression of chondrocyte differentiation. However, the mechanistic basis for the antichondrogenic activity of Twist1 has not heretofore been established. Here, we show that Twist1 suppresses cartilage development by directly inhibiting the transcriptional activity of Sox9, the master regulator of chondrogenesis.Twist1, through its carboxyl-terminal Twist-box, binds to the Sox9 HMG DNA-binding domain, >> inhibiting Sox9 transactivation potential <<. In chondrocyte precursor cells, Twist1, in a Twist-box-dependent manner, >> inhibits Sox9-dependent activation of chondrocyte marker gene expression << by blocking Sox9-enhancer >> DNA association<<.
No matter how much sox9 you have, it won't matter because TWIST1 stops DNA activation and negates the SOX9. Cell basics 101
Yeah but in the LSJL gene expression study they didn't find that TWIST1 was affected by LSJL. And Twist1 has an affect on osteoblasts too.
DeleteI wasnt really referring to LSJL. TWIST1 is activated by the canonical WNT pathway, and a variety of hormones activate the canonical WNT pathway, most notably being the sex steroids. Pituitary tumours that result in suraphysical growth hormone emissions should in theory be capable of inducing high levels of SOX9, but this doesn't necessarily mean there will be chondrogenesis because the TWIST1 pathway can and will prevent nuclear SOX9 DNA activation. Meaning, no matter how much sox9 you have, you would need to inhibit twist1 activity in order to let SOX9 exert it's effects. Like, some people with acromegaly don't really end growing after their growth plates fuse.
Deletetgf-b increases sox9 levels while it also increases twist1. Since an increase in sox9 was seen, even when it also increased a sox9 DEcreasing gene you should stop wasting your time on this useless study
ReplyDeleteok, but you cant say it is totally useless, as it plays a part in chondrocyte gene expression and is effected by igf1. we need to upregulate sox9 without upregulating twist.
enhanced CNP expression inhibits FGF-2-mediated activation of ERK MAP kinase / ERK 1/2 / MEK 1 in general.
ReplyDeleteThis negates the effect of IGF-1 on twist1 expression.
hey guys is this a new drug to increase height or just study and research..???
ReplyDeletei want to buy these therapy or tablet to increase my height
i am 30 year old doctor in IL
Please make sure to not accept information from a site/a user who advises strong Aromatase Inhibitors in his stacks or blogs, to completely block estrogen for height increase.
ReplyDeleteBlocking Estrogen will result in stunted growth, leaving you shorter.
Announce this in one of your articles to make sure that no one takes these "Stacks", to guarantee their own safety
There are several articles about estrogen on this site. And they all recommend an equilibrium quantity of estrogen. As both too much and too little estrogen is bad for height.
DeleteSo alphagenetik does this mean the following study is not valid?
Deletehttp://www.ncbi.nlm.nih.gov/pubmed/20164294
CONCLUSIONS:
DeleteOur findings indicate that in adolescent boys an increase in adult height can be attained by use of aromatase inhibitors.
http://www.ncbi.nlm.nih.gov/pubmed/16649968
Results of a randomized placebo-controlled trial in boys with delayed puberty treated with letrozole, a selective nonsteroidal AI, found that boys treated with letrozole + testosterone experienced delayed bone maturation and good growth response and achieved an increase in predicted adult height.
http://www.ncbi.nlm.nih.gov/pubmed/16766117
Take in account what I said before.
ReplyDeleteEnhanced CNP expression inhibits ERK MAP Kinase.
If this pathway is blocked, then IGF-1 won't cause an increase of twist1.
This is sufficient to enable chondrogenesis, case closed.
Some websites like heightcatalyst still struggle with something like twist1, so better research on your own.
This will just slow you down.
But I thought the canonical wnt pathway stimulates twist1? What has that got to do with IGF-1?
ReplyDeleteWhere do we get this "Enhanced CNP expression"?
ReplyDelete