Growing Taller with natriuretic peptides?

Good to see they are in testing for a CNP treatment(BMN111).  I don't know how it will integrate with LSJL(since ERK signaling may be needed for initial chondroinduction) but it's great for open growth plates.

Evaluation of the Therapeutic Potential of a CNP Analog in a Fgfr3 Mouse Model Recapitulating Achondroplasia

"C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK){MAPK pathway has anabolic effects too so it's not as simple as inhibiting it}. We report the pharmacological activity of a 39 amino acid CNP analog (BMN 111) with an extended plasma half-life due to its resistance to neutral-endopeptidase (NEP) digestion. In ACH human growth-plate chondrocytes{so note this was in existing chondrocytes, ERK exerts most of it's benefits on the early stages of chondrocyte lineage before stem cells become full fledged chondrocytes}, we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2, confirming that this CNP analog inhibits fibroblast-growth-factor-mediated MAPK activation. Concomitantly, we analyzed the phenotype of Fgfr3(Y367C/+) mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3(Y367C/+) mice, treatment with this CNP analog led to a significant recovery of bone growth. We observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect. Thus, our results provide the proof of concept that BMN 111, a NEP-resistant CNP analog, might benefit individuals with ACH and hypochondroplasia."

"Binding of CNP to its receptor, natriuretic-peptide receptor B (NPR-B), inhibits FGFR3 downstream signaling at the level of Raf-1 and thus triggers endochondral growth"

"We observed NPR-B localization in the proliferative and hypertrophic zones of human control, ACH, and TD growth plates"

"In growth-plate histology sections of Fgfr3Y367C/+ and Fgfr3+/+ mice, we observed FGFR3 and NPR-B localization in the proliferative and hypertrophic zones of the cartilage "

800 micrograms/kg of bodyweight of BMN111 to mice for 10 days increased tibia and femur length by 5-7%.

Here's information on the product pipeline from Biomarin.  Information on the testing of the substance for dwarfism.  Even though it's tested on dwarfism it will work to increase height growth as long as you have FGFR3 and have open growth plates.

"In 2012, BioMarin initiated a Phase 1 study, which is being conducted in adult volunteers without Achondroplasia, to inform the starting dose and regimen for future studies. A Phase 2 pediatric study in children with Achondroplasia is scheduled to start in the last quarter of 2012 or the first quarter of 2013."<-If the adults grew taller we can see if Alkcolars theory that CNP can initiate height growth was correct.

"Enrolling males without Achondroplasia ages 22 to 45 years with a body weight between 63 and 100 kg.  The study will last for 4 or 17 consecutive days and nights."<-not a lot of time to observe height growth.

Here's more details on the study for adults.  The study should have been completed on June 2012 but no results have been posted.

There's a patent pending on free patents online for a new height increase product called a "composition for increasing body height":

"This invention provides a composition for increasing a body height of a patient with short stature or an individual other than patients with short stature. More specifically, the invention provides: a composition for increasing the body height of an individual comprising a guanyl cyclase B (GC-B) activator as an active ingredient, the composition being to be administered to an individual free from FGFR3 abnormality; a method for increasing the body height of an individual free from FGFR3 abnormality which comprises activating GC-B[I don't know if GC-B will increase height on it's own without additional cGMP]; a method for screening an agent for increasing the body height of an individual which comprises selecting an agent for increasing the body height using GC-B activity as an indication; and a method for extending a cartilage bone free from FGFR3 abnormality which comprises activating GC-B in an individual."

"Guanyl cyclase (GC) is a membrane protein belonging to the enzyme family that catalyzes the synthesis of the second messenger cGMP from GTP. GC-B is found mainly in vascular endothelial cells, and thought to be involved in relaxation of the smooth muscle."

"Natriuretic peptides (NPs) are divided into ANP (atrial sodium peptide), BNP (brain natriuretic peptide) and CNP (type c natriuretic peptide), and they are thought to elevate an intracellular cGMP level through two guanyl cyclase conjugated receptors (NPR-A for ANP and BNP, and NPR-B for CNP) and to perform intracellular signal transduction mediated by a plurality of cGMP effecter molecules. NPs have been reported to play an important role in the control of humoral homeostasis and blood pressure, and their expression and biological activity in various tissues other than the cardiovascular system are known. Concerning cartilage bones, effectiveness of overexpression of BNP or CNP in the joints on the treatment of achondrogenesis resulting from mutation of a fibroblast growth factor receptor 3 (FGFR3) gene has been reported."

"We have prepared a C-type natriuretic peptide (CNP) transgenic mouse, which expresses CNP, a guanyl cyclase B (GC-B) activator, systemically with elevated blood level of CNP, and then studied the effect of CNP on body height or on growth cartilage. As a result, we have now found that in the CNP transgenic mouse the increase in body height is accelerated, that the femoral growth plate cartilage becomes significantly thickened, and that, through the property analyses of such CNP transgenic mice, the increase in body height is accelerated by the effect of CNP on hematogenously in the absence of an abnormality in FGFR3."

Now remember an acceleration of height gain does not necessarily mean an increase in final adult height.

"The thickness of the growth cartilage of CNP Tgm(CNP transgenic mice) was histologically analyzed using the mean thickness of the resting layer, proliferating layer and hypertrophy layer of the growth cartilage on the patellar surface femur, and the total of the three layers (as the thickness of growth cartilage). As a result, it was confirmed that each thickness of the resting layer, proliferating layer and hypertrophy layer, and the total thickness thereof for CNP Tgm were greater with statistical significance than those of the wild type. It was also demonstrated that CNP accelerates the increase in body height in animals by increasing each thickness of the resting layer, proliferating layers and hypertrophy layer of other cartilage bones, such as the tibiae, radiuses or ulnae, in addition to those of the cartilage bone of femora."

Now C-type natriuretic peptide affects the resting layer which might be the limiting factor in terms of height growth.  Therefore, this supplement does have potential to increase height since it does act locally on the growth plate and affects the starting stage of growth.

"In the present invention, the term “FGFR3 abnormality” refers to achondrogenesis or achondroplasia, which is caused by growth inhibition of cartilage bones resulting from mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, or achondrogenesis or achondroplasia caused by function control failure of FGFR3 or overexpression of FGFR3 gene resulting from mutations in the FGFR3 gene."

I don't get what a cartilage bone is.  Maybe it refers to a long bone which has cartilage in the growth plate.

There are lots of studies that state that C-type natruiretic peptides are essential in growth and can account for growth variation like this one:


A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation. 


"Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (P(combined) = 3.4 x 10(-9)). Notably, a second SNP (rs6718438) located approximately 450 bp away and in strong LD (r(2) = 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (P(combined) = 2.1 x 10(-7)). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height." 

So yes maybe guanyl cyclase activator could increase height.  In adults it's unclear if manipulation of the C-type natriuretic peptide signaling pathway could "re-awaken the growth plates".  Someone like alkoclar claims that enhancing CNP expression has the ability to increase adult height.

Here's a study that shows that CNP causes skeletal overgrowth during development:

C-Type Natriuretic Peptide and Overgrowth

"Natriuretic peptides are a family of structurally related peptides with different distinct biological effects. C-type natriuretic peptide (CNP)-mediated signaling is important for endochondral ossifica-tion and intervenes in the control of chondrocyte maturation by regulating the balance between proliferation and terminal differentiation[there's no proliferating chondrocytes in adults so how would CNP increase adult height?  Unless you cause the differentiation of stem cells into chondrocytes with LSJL]. CNP is encoded by the NPPC gene on human chromosome 2 for which, so far, no mutations have been described in humans. Recently, two independent articles reported the description of 3 patients with a similar clinical phenotype characterized by the pres-ence of skeletal anomalies and overgrowth. In all 3 cases, the clinical picture was associated with the presence of a balanced translocation involving chromosome 2 and causing overexpression of the NPPC gene and an increased plasma concentration of its product, CNP[to cause skeletal overgrowth in development increase plasma concentration of CNP]. Transcriptional dysregulation of NPPC has been ascribed to the separation of the gene unit from the long-range regulatory element with a transcriptional silencing effect on its expression and CNP overproduction has been correlated to the skeletal overgrowth phenotype observed."

In the study "Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and boneanomalies in an individual with balanced t(2;7) translocation" overexpression of CNP in osteoblastic cells in mice resulted in skeletal overgrowth this supports the theory that increasing CNP plasma levels can increase skeletal size as adults definitely have osteoblastic cells.

Here's an article about achondroplasia(dwarfism) and how CNP may be a possible cure:

"[CNP acts by inducing intracellular cGMP through Guanylyl Cyclase B]"

"genetically engineered mice have short bones when null for CNP and long bones when CNP is overexpressed"<-is this dose dependent however?  Would more CNP increase height indefinitely at higher and higher levels?

"growth plates in these mice are shortened and widened [in CNP over- and -under expression] in a manner similar to that detected in mice with loss- and gain-of-function mutations for FGFR3"<-FGFR3 gain-of-function causes dwarfism.

"transgenic mice [were generated] in which CNP was overexpressed in the growth plate; expression of the gene encoding CNP, designated Nppc, was driven by the type II collagen cartilage-specific promoter (Col2). The Col2-Nppc transgenic mice displayed excessive skeletal growth that was mainly postnatal[after birth]."<-So more Type II Collagen more CNP?

"Offspring of the mating that carried both the Col2-Nppc and Col2-FGFR3 transgenes had near normal body lengths when measured over 10 weeks"

"the over-expression of CNP did not appear to rescue the reduced proliferation of growth plate chondrocytes detected in the Col2-FGFR3"<-meaning that possibly the amount of proliferation of growth plate chondrocytes does not have much affect on height.  Or, it's possible that the positive benefits of CNP overexpression are greater than the effects of FGFR3 overexpression.

"[cultured tibias were treated] from Col2-FGFR3 ach mice with different doses of CNP. Bone length showed a dose response to the CNP"<-But we can't be sure that this dose response occurs forever.

"The dose that restored bone length to normal also restored synthesis of 2 markers of cartilage matrix biosynthesis(glycosaminoglycan and collagen),which were reduced in the Col2-FGFR3 mice, to near normal"<-so cartilage matrix is likely the best determinant of height and not chondrocyte proliferation.  That means that something like High Molecular Weight Hyaluronic Acid could possibly increase height during puberty.

"FGFR3 signals through STAT1 to down regulate chondrocyte proliferation and differentiation and through the MAP kinase-ERK pathway to negatively control matrix synthesis in the growth plate. They propose that CNP blocks the MAP kinase inhibitory signals of FGFR3 to increase matrix synthesis and thereby counters the restraining consequences of FGFR3 on bone growth"<-So other possible target proteins for height increase are STAT1 and MAPK inhibitory signals.

Dose dependent effect of C-type natriuretic peptide signaling in glycosaminoglycan synthesis during TGF-β1 induced chondrogenic differentiation of mesenchymal stem cells.

"This study investigated the role of CNP in transforming growth factor (TGF)-β1 induced in vitro chondrogenic differentiation of mesenchymal stem cells (MSCs) in pellet culture. MSCs were derived from human trabecular bone and were characterized on the basis of their cell surface antigens and adipogenic, osteogenic, and chondrogenic differentiation potential. TGF-β1 induced chondrogenic differentiation[our goal is to induce mesenchymal chondrogenesis in the trabecular bone, so it's good news that TGF-Beta1 induced chondrogenic differentiation there] and glycosaminoglycan (GAG) synthesis was analyzed on the basis of basic histology, collagen type II, Sox 9 and aggrecan expressions, and Alcian blue staining. Results revealed that human trabecular bone-derived MSCs express CNP and NPR-B analyzed on the basis of RT-PCR and immunohistochemistry. In pellet cultures of MSCs TGF-β1 successfully induced chondrogenic differentiation and GAG synthesis. RT-PCR analyses of both CNP and NPR-B during this process revealed an activation of this signaling pathway in response to TGF-β1. Similar cultures induced with TGF-β1 and treated with different doses of CNP showed that CNP supplementation at 10(-8) and 10(-7) M concentrations significantly increased GAG synthesis in a dose dependent manner, whereas at 10(-6) M concentration this stimulatory effect was diminished. In conclusion, CNP/NPR-B signaling pathway is activated during TGF-β1 induced chondrogenic differentiation of human trabecular bone-derived MSCs and may strongly be involved in GAG synthesis during this process. This effect is likely to be a dose-dependent effect."

"Studies on natriuretic peptides utilizing genetically altered mice revealed that there is no detectable skeletal phenotype in ANP, BNP, and NPR-A knockout mice, whereas CNP and NPR-B knockout mice were severely dwarfed in comparison to control group"

"CNP-3 [is] an autocrine/paracrine factor acting trough NPR-B and [is involved] in the process of early pre-chondrogenic mesenchymal condensation, GAG synthesis, and late differentiation, i.e., maturation and hypertrophy, of chondrocytes."

"The expression of NPR-B was more abundant than that of CNP in MSCs."

"Results revealed that TGF-β1 induction of human MSCs in pellet cultures increased the low expression profile of CNP mRNA and NPR-B precursor in control group detected at day-4 of incubation"

"Mapping of the Nppc promoter showed an enhancing binding site for TSC22{TSC22d3(more commonly called Gilz) is down in LSJL}, a transcription factor that is an early response gene to TGF-β"

CNP should only help during development.  After development, you would need to induce a new cartilagenous matrix followed by endochondral ossification.

An Overgrowth Disorder Associated with Excessive Production of cGMP Due to a Gain-of-Function Mutation of the Natriuretic Peptide Receptor 2 Gene.

"We describe a three-generation family with tall stature, scoliosis and macrodactyly of the great toes and a heterozygous p.Val883Met mutation in Npr2, the gene that encodes the CNP receptor NPR2 (natriuretic peptide receptor 2). When expressed in HEK293A cells, the mutant Npr2 cDNA generated intracellular cGMP (cyclic guanosine monophosphate) in the absence of CNP ligand. In the presence of CNP, cGMP production was greater in cells that had been transfected with the mutant Npr2 cDNA compared to wild-type cDNA. Transgenic mice in which the mutant Npr2 was expressed in chondrocytes driven by the promoter and intronic enhancer of the Col11a2 gene exhibited an enhanced production of cGMP in cartilage, leading to a similar phenotype to that observed in the patients. In addition, blood cGMP concentrations were elevated in the patients. These results indicate that p.Val883Met is a constitutive active gain-of-function mutation and elevated levels of cGMP in growth plates lead to the elongation of long bones."

"Upon CNP binding, its cognate receptor natriuretic peptide receptor 2 (NPR2) functions as a guanylyl cyclase to increase cyclic guanosine monophosphate (cGMP) levels in chondrocytes"

"The increase in cGMP level activates cGMP-dependent protein kinase II and seems to promote the accumulation of extracellular matrix in the growth plate of CNP-transgenic mice"

"Histological examination confirmed that the skeletal overgrowth was caused by the widening of the growth plates in the transgenic mice expressing the mutant Npr2"<-So maybe any method that increases growth plate width will increase height?

"Although NPR2 is expressed in various tissues, the phenotype seems to be confined to cartilage and bone in humans"<-So increasing cGMP levels shouldn't cause issues in other tissues.  Although Viagra increases cGMP and it causes effects in non-bony tissues.

C-type natriuretic peptide regulates cellular condensation and glycosaminoglycan synthesis during chondrogenesis.

"CNP has been shown to stimulate proliferation and hypertrophic differentiation of growth plate chondrocytes.  CNP increases the number of chondrogenic condensations of mouse embryonic limb bud cells in micromass culture. This is accompanied by increased expression of the cell adhesion molecule N-cadherin. In addition, CNP stimulates glycosaminoglycan synthesis as indicated by increased Alcian blue staining. However, expression of the chondrogenic transcription factors Sox9, -5, and -6 or of the main extracellular matrix genes encoding collagen II and aggrecan is not affected by CNP. Instead, we show that CNP increases expression of enzymes involved in chondroitin sulfate synthesis, a required step in the production of cartilage glycosaminoglycans."

"Npr3, is thought to act as a decoy/scavenger receptor that limits CNP effects by removing it. Npr3−/− mice display skeletal overgrowth"

"loss-of-function mutations in the human NPR2 gene result in idiopathic short stature"

"cGMP activates cyclic nucleotide phosphodiesterases, cGMP-regulated ion channels, and cGMP-dependent protein kinases. CNP and cGMP have been determined to stimulate longitudinal growth of long bones"

"CNP treatment results in an increased expression of transcripts for N-cadherin, link protein, xylosyltransferase I, Chst11, and Chst3."

"both CNP and cGMP give rise to significantly more nodules than control cultures relative to total protein"

"CNP preferentially stimulates condensations and GAG synthesis without parallel effects on other aspects of chondrogenesis."

Sox9 was used in the study.  A real test to see if CNP could induce chondrogenesis is using a Sox9-null mice and increasing CNP to see if chondroinduction was possible.

Characterization of novel 3'untranslated regions and related polymorphisms of the gene NPPC, encoding for the C-type natriuretic peptide.

Lists several miRNA's that can manipulate the NPPC gene.

Acute inflammation in young children inhibits C-type natriuretic peptide

"C-type natriuretic peptide (CNP) is a paracrine growth factor critical in endochondral bone growth. Amino-terminal CNP (NTproCNP), measurable in plasma, correlates with growth-plate activity and can be used as a biomarker of height velocity in children. Because severe inflammation in adults increases CNP{so could inflammation be a key to adult height growth although CNP doesn't start the growth plates it merely increases chondrocyte hypertrophy resulting in additional height}, we studied CNP peptides and inflammatory markers in children with acute illness.
Forty-two children aged 2 months to 5 years with acute illness warranting admission to an acute assessment unit were studied. Fifteen age-matched well children attending an outpatient clinic served as controls. Venous CNP concentrations were measured at admission, along with markers of acute inflammation (body temperature, C-reactive protein (CRP) and white blood cell count) in children with acute illness.
NTproCNP and CNP standard deviation scores (SDS) in the acutely ill group were significantly suppressed compared to well children or to healthy population norms. NTproCNP SDS was significantly inversely related to body temperature and CRP.
Acute inflammation in young children potently reduces CNP production which needs to be considered when screening for growth disorders. The adverse effects of inflammatory cytokines on skeletal growth may be mediated in part by reduced CNP."

Unfortunately I couldn't get this full article.

Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations.

"The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient."

Exercise can increase CNP levels in people with diabetes:

Effects of exercise intervention on vascular endothelium functions of patients with impaired glucose tolerance during prediabetes mellitus.

"Exercise intervention increased CNP levels, decreased ET-1 levels and increased ΔDia-P, indicating improved vascular endothelium function."

In the control group, however CNP levels stayed the same.  In Diabetes group CNP levels increased by about 15%.  CNP levels increased even more in the diabetes group with the addition of resistance training.  CNP levels were relatively the same pre-exercise in both the control and diabetes group.

"vascular endothelial cells (ECs) are able to synthesize and secrete a variety of bioactive factors, including ET-1 and CNP"

Differential Effects of Natriuretic Peptide Stimulation on Tissue-Engineered Cartilage

"Tissue engineering is a promising approach for articular cartilage repair; however, it still has proven a challenge to produce substantial quantities of tissue from the limited number of cells that can be extracted from a single individual. Although several approaches have been investigated to enhance the production of cartilaginous tissue in vitro, relatively few techniques exist to reliably increase the population of cells needed for this approach. Alternatively, a single modulator of chondrocyte function, such as the C-type natriuretic peptide (CNP), may serve to address both of these issues. CNP is expressed in the growth plate and regulates cartilage growth through chondrocyte proliferation and differentiation. Thus, the purpose of this study was to determine the effects of CNP stimulation on tissue-engineered cartilage. Isolated bovine articular chondrocytes[If CNP can stimulate articular cartilage it can possibly increase height in adults] were seeded on MillicellTM filters and cultured in the presence of CNP (10 pM to 10 nM) for 4 weeks. Stimulation with CNP resulted in differential effects depending on the dose of the peptide. Low doses of CNP (10 to 100 pM) elicited chondrocyte proliferation with a maximal response observed at 100 pM (43% increase in cellularity). However, high doses of CNP (10 nM) stimulated matrix deposition (36% and 137% increase in proteoglycans and collagen) without an associated change in tissue cellularity. CNP stimulation also downregulated the expression of type X collagen, an early hypertrophic marker associated with endochondral ossification. Thus, by regulating the dose of CNP, it may be possible to produce engineered tissue from the limited number of cells that can be reasonably extracted from a single individual for therapeutic purposes."

This is tissue engineered cartilage so real results may differ.

Be Taller with Nitric Oxide?

LSJL genes involved with Nitric Oxide:

Superoxide(byproduct of free radicals and Nitric Oxide):
Sod3{up}(Superoxide Metabolism)
Nox1{up}(Superoxide Release)

Nitric Oxide:
Ddah1{up}(nitric oxide biosynthesis)
Mt1{up}(Nitric Oxide mediated signal transduction)
Mt2{up}(Nitric Oxide mediated signal transduction)

Free Radicals:
Me3{up}(oxygen and reactive oxygen species metabolic process)

There are several ways that mechanical load influences bone growth.  How is Nitric Oxide involved in this process and can we manipulate Nitric Oxide to be taller people? 

Endothelial nitric oxide synthase deficiency results in reduced chondrocyte proliferation and endochondral bone growth. 

"[What are the[ effects of inactivation of endothelial nitric oxide synthase (eNOS) on cartilage development in mice?  Skeletal growth and development of mice carrying a null mutation in the eNOS gene was studied in comparison to control littermates. In situ analyses were complemented by experiments with primary chondrocytes and tibial explants from these mice. eNOS-deficient mice show increased lethality and reduced bone growth, with hypocellular growth plates and a marked reduction in the number of proliferating chondrocytes. In vitro studies demonstrated lower chondrocyte numbers and reduced endochondral bone growth in mutants, suggesting that the role of eNOS signaling in chondrocyte proliferation is cell-autonomous[Meaning that the mutation is local per cell rather than system wide]. Reduced chondrocyte numbers appear to be caused by decreased cyclin D1 and increased p57 expression in mutants, resulting in slower cell cycle progression and earlier cell cycle exit. In addition, expression of early chondrocyte markers such as Sox9 was reduced and prehypertrophic markers were expressed prematurely in mutant mice. eNOS [has a role] in chondrocyte proliferation and endochondral bone growth. Loss of eNOS results in premature cell-cycle exit and prehypertrophic chondrocyte differentiation during cartilage development." 

"NO is synthesized through l-arginine by NO synthases (NOS) in many cell types. Three different types of NOS have been identified. The neuronal NOS (nNOS or NOS1) and endothelial NOS (eNOS or NOS3) forms are constitutively expressed, and their activity is regulated by intracellular signaling and the calcium-binding protein calmodulin. The inducible form (iNOS or NOS2) is stimulated at the level of expression by factors including lipopolysaccharide and cytokines, such as interleukin-1, tumor necrosis factor α, and interferon-α, and leads to sustained and high levels of NO, mainly in inflammatory disease"

"NO signaling promotes chondrocyte hypertrophy"

"reduced numbers of cells in the proliferative zone are a general feature of eNOS−/− bones"

"the transcription factor ATF-3 is up-regulated during chondrocyte hypertrophy and represses the activity of the cyclin D1 promoter in chondrocytes. ATF-3 expression [increases] in eNOS-deficient growth plates, suggesting that premature induction of ATF-3 expression in mutant mice leads to repression of cyclin D1 transcription and chondrocyte proliferation."<-LSJL heavily upregulates ATF3.

"eNos deficiency [promotes] prehypertrophic gene expression. [Analysis of] neonate cartilage revealed decreased expression of the early chondrocyte markers Col2a1 and Sox9, and increased expression of the prehypertrophic markers RORa and Hif1a in the cartilage of eNOS-knockout mice."

"Both NO and CNP stimulate the production of cGMP via soluble or particulate guanylyl cyclases, these similarities provide further evidence of the importance of cGMP signaling in endochondral bone formation. However, the phenotype of eNOS-null mice does not exactly resemble that of mice lacking CNP or the main effector of cGMP in cartilage, cGMP-dependent kinase II. For example, mice lacking CNP have strikingly narrow growth plates and shorter proliferating and hypertrophic zones "

These results are echoed by this study Reduced chondrocyte proliferation, earlier cell cycle exit and increased apoptosis in neuronal nitric oxide synthase-deficient mice.  In this study chondrocytes with neurol nitric oxide deficiency, expressed more c-Fos, ATF3, and ROR-alpha(which inhibits chondrogenesis). Also, eNos and iNos levels were increased in nNOS KO mice.  The study also noted that they did not notice the phenotype change of the a decrease in length of the hypertrophic zone which is typical in CNP null mice.  The speculated that eNos and iNos may compensate for decreased nNos levels.

Now, Nitric Oxide appears to be only beneficial if you have sufficient quantities of the enzyme whereas exercise Nitric Oxide seems like it wouldn't have an additional effect.  Perhaps increasing Cyclin D1 and decreasing p57 can result in supernatural growth.  Nitric Oxide can be affected by exercise... 

Effect of low-magnitude, high-frequency vibration on osteocytes in the regulation of osteoclasts. 

"Osteocytes are  the major mechanosensor in bone, responsible for sending signals to the effector cells (osteoblasts and osteoclasts) that carry out bone formation and resorption. osteocytes release various soluble factors (e.g. transforming growth factor-beta, nitric oxide, and prostaglandins) that influence osteoblastic and osteoclastic{and possibly chondrocytes} activities when subjected to a variety of mechanical stimuli, including fluid flow[LSJL but we're more interested in the effects of chondrocytes but this might mean that direct loading of the spinous process of your vertebrae may increase your height], hydrostatic pressure, and mechanical stretching. Low-magnitude, high-frequency (LMHF) vibration (e.g., acceleration less than <1 x g, where g=9.81m/s(2), at 20-90 Hz) can positively influence skeletal homeostasis in animals and humans. Osteocytes are the mechanosensor responsible for detecting the vibration stimulation and producing soluble factors that modulate the activity of effector cells.  We applied low-magnitude (0.3 x g) vibrations to osteocyte-like MLO-Y4 cells at various frequencies (30, 60, 90 Hz) for 1h. Osteocytes were sensitive to this vibration stimulus at the transcriptional level: COX-2 maximally increased by 344% at 90Hz, while RANKL decreased most significantly (-55%, p<0.01) at 60Hz[RANKL increases osteoclast activity]. Conditioned medium collected from the vibrated MLO-Y4 cells attenuated the formation of large osteoclasts (> or =10 nuclei) by 36% and the amount of osteoclastic resorption by 20%. The amount of soluble RANKL (sRANKL) in the conditioned medium was found to be 53% lower in the vibrated group, while PGE(2) release was also significantly decreased (-61%)." 

"osteocytes have been found to communicate with effector cells through gap junctions and soluble factors"<-these soluble factors may promote chondrocyte differentiation as well.

" PGE2 promotes the differentiation of osteoclasts in bone marrow cultures"

"PGE2 released by bone cells has been found to increase upon fluid flow stimulation and mediate downstream responses such as increased expression of gap junction protein connexin (Cx) 43"

LMHF increased Cox2 but decreased PGE2.

Now, vibrations on the bone can be simulated by impact with exercises like jumping or tapping.  

Nitric Oxide can only help in lengthening short, irregular, and flat bones as it affects osteoblasts and not chondrocytes(although there may be a yet unknown effect on chondrocytes).  Nitric Oxide is one of the factors released by osteocytes in response to various mechanical strain. Nitric Oxide is affected by exercise as a result of fluid flow on the bone(lateral synovial joint loading which on non-long bones is any direction).   

This also means that Lateral Synovial Joint Loading should result in bigger epiphysis of your long bones(bigger ankles/wrists) as the epiphysis is basically a short bone attached to hyaline cartilage.  

Inducible nitric oxide synthase-nitric oxide signaling mediates the mitogenic activity of Rac1 during endochondral bone growth.

"chondrocyte-specific deletion of the gene Rac1 in mice leads to severe dwarfism due to reduced chondrocyte proliferation. Rac1-deficient chondrocytes have severely reduced levels of inducible nitric oxide synthase (iNOS) protein and nitric oxide (NO) production. NO donors reversed the proliferative effects induced by Rac1 deficiency, whereas inhibition of NO production mimicked the effects of Rac1 loss of function[so proper NO levels are essential to grow taller]. The growth plate of iNOS-deficient mice [have] reduced chondrocyte proliferation and expression of cyclin D1, resembling the phenotype of Rac1-deficient growth plates.  Rac1-NO signaling inhibits the expression of ATF3, a known suppressor of cyclin D1 expression in chondrocytes[note that ATF3 is upregulated by LSJL so perhaps when performing LSJL NO signaling has to be enhanced to counteract the upregulation by LSJL]. "

"Rac1 promotes chondrocyte proliferation through iNOS–NO-mediated induction of cyclin D1 expression."

So for optimal LSJL effectiveness you need to stimulate NO expression to counteract the increase in ATF3. Although ATF3 may help in forming in growth plates.

Inorganic phosphate induces mammalian growth plate chondrocyte apoptosis in a mitochondrial pathway involving nitric oxide and JNK MAP kinase.

"Chondrocytes in the hypertrophic zone of the growth plate undergo apoptosis during endochondral bone development via mechanisms that involve inorganic phosphate (Pi) and nitric oxide (NO){apoptosis may not necessarily be bad for height growth though}. Pi-dependent NO production plays a role in apoptosis of cells in the resting zone as well.  Pi decreased the number of viable cells; the number of TUNEL-positive cells and the level of DNA fragmentation were increased, indicating an increase in apoptosis. Blocking NO production using the NO synthase (NOS) inhibitor L: -NAME or cells from eNOS(-/-) mice blocked Pi-induced chondrocyte apoptosis, indicating that NO production is necessary. NO donors NOC-18 and SNOG both induced chondrocyte apoptosis. SNOG also upregulated p53 expression, the Bax/Bcl-2 expression ratio, and cytochrome c release from mitochondria, as well as caspase-3 activity, indicating that NO induces apoptosis via a mitochondrial pathway. Inhibition of JNK, but not of p38 or ERK1/2, MAP kinase was able to block NO-induced apoptosis, indicating that JNK is necessary in this pathway. Pi elevates NO production via eNOS in resting zone chondrocytes, which leads to a mitochondrial apoptosis pathway dependent on JNK."

"Pi induced a concentration-dependent increase in caspase-3 activity, with 7.5 mM Pi causing a 3.4-fold increase compared with control culture"

"Pi regulated p53 abundance in resting zone chondrocytes. Although 2.5 mM Pi did not significantly increase p53, 5 and 7.5 mM Pi treatment increased p53 protein 2.6- and 2.8-fold, respectively. Pi also induced a concentration-dependent increase in levels of Bax and a concentration-dependent decrease in levels of Bcl-2. The Bax/Bcl-2 ratio was greatest in cultures treated with 7.5 mM exogenous Pi, with a sixfold increase compared to control."

Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content.

"eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored umbilical cord to childhood bone size and density in a group of 9-year-old children. We  assess the methylation status of two CpGs in the eNOS promoter in stored umbilical cords of 66 children who formed part of a Southampton birth cohort and who had measurements of bone size and density at age 9 years. Percentage methylation varied greatly between subjects. For one of the two CpGs, eNOS chr7:150315553 + , after taking account of age and sex, there were strong positive associations between methylation status and the child's whole-body bone area, bone mineral content, and areal bone mineral density at age 9 years. These associations were independent of previously documented maternal determinants of offspring bone mass.  An association [exists] between methylation status at birth of a specific CpG within the eNOS promoter and bone mineral content in childhood. eNOS [has a role] in bone growth and metabolism."

Unfortunately bone length was not measured.