Enhance your Height by stimulating Twist1

The new site Height Catalyst has a new height increase modality that involves inhibiting Twist1.  Twist1 inhibits chondrogenesis.  How can we inhibit Twist1?  How does Twist1 work to inhibit chondrogenesis?  Twist1 may actually inhibit chondrogenesis but may be beneficial to chondrocyte hypertrophy thus Twist1 may increase height but may be an obstacle to chondroinduction by LSJL.

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."

"Twist1 is an essential and multifunctional protein implicated in a diverse range of normal and pathological processes spanning development and differentiation to congenital malformation syndromes and cancer."<-So we want to try to inhibit Twist1 specifically in the bone.  Although Twist1 is actually involved in Cancer so inhibition of Twist1 may actually be anti-carcenogenic.

"In mammals, Twist1 is developmentally expressed in mesoderm-derived embryonic tissues and postnatally in adult mesoderm-derived mesenchymal stem cells where it functions as a major regulator of mesenchymal cell differentiation "<-So we want to try to inhibit Twist1 in bone MSCs

"Twist1, through its C-terminal Twist-box, binds directly to the Sox9 HMG DNA-binding domain, leading to inhibition of Sox9-dependent gene activation"<-So finding a compound that binds to Twists1's C-terminal Twist box may block it from binding to Sox9.

Having a high bodyfat percentage may help decrease Twist1 levels:

Twist1 in human white adipose tissue and obesity.

"Twist1 is a transcription factor implicated in the regulation of TNFα signaling and [is] highly expressed in both human and murine adipose tissue.
[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.

Insulin-like growth factor 1 (IGF-1)-induced twist expression is involved in the anti-apoptotic effects of the IGF-1 receptor.

"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 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"