This treatment mostly looks applicable to those pre skeletal maturity but there is the possibility to inject new skeletal stem cells.

Stimulation of skeletal stem cells in the growth plate promotes linear bone growth

“skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs). Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1^fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.”
According to this paper Mechanotransduction pathways in the regulation of cartilage chondrocyte homoeostasis, “Mechanical stress up‐regulates Indian hedgehog expression (IHH) and activates hedgehog (Hh) signaling” “cyclic tensile strain activates Hh signaling and promotes the expression of ADAMTS‐5 in a primary cilia‐dependent manner, but in a high strain environment, histone deacetylase 6 (HDAC6) causes cilial disassembly and blocks this response”<-So we could potential mimic some of the effects of this study with mechanical loading because it also activates the hedgehog pathway but not too much activation as it blocks the mechanical loading benefits to hedgehog. So potentially with the right mechanical loading we could mimic the benefits of this study.

From the above picture, any method of increasing hedgehog signaling will work including potentially mechanical loading.

“Morphologically and functionally, the growth plate can be divided into the resting, proliferative, and hypertrophic zones. The resting zone contains slowly cycling cells, which, upon recruitment into the underlying proliferative zone, begin proliferating rapidly and arrange themselves into longitudinal columns of flat chondrocytes. Thereafter, these flat chondrocytes undergo further differentiation along with hypertrophy, forming the hypertrophic zone. Thereafter, the hypertrophic chondrocytes die or transdifferentiate, leaving a cartilaginous template on which spongy bone is built.”

“The resting zone contains a unique population of stem cells that express the parathyroid hormone–related protein (PTHrP). Furthermore, these stem cells reside in a niche that governs their abilities of renewal and generation of transit-amplifying proliferative chondrocytes. Interestingly, this niche arises postnatally, probably in association with maturation of the SOC, and only then can the stem cells obtain self-maintaining capacity and the ability to produce stable, long-lasting clones”

“

The importance of the Hedgehog (Hh) signaling pathway in development of the skeleton is demonstrated by the observation that deletion of Indian hedgehog (Ihh) (normally expressed by prehypertrophic and hypertrophic chondrocytes), either globally or specifically in cartilage, virtually eliminates formation of the growth plate. Together with PTHrP, Ihh is involved in a negative-feedback loop that controls the rate of chondrocyte differentiation. More specifically, Ihh produced by prehypertrophic and hypertrophic chondrocytes diffuses to the resting zone, where it stimulates expression of PTHrP, which in turn inhibits the hypertrophic differentiation of chondrocytes.

In addition, if Hh signaling is inhibited either genetically within the growth plate or pharmacologically during postnatal growth, the growth plate fuses abruptly“<-can we manipulate hedgehog signaling to keep the growth plate open for longer?

” Hh signaling stimulates the proliferation and clonal activity of epSSCs independent of age.”<-this is very promising for being able to potentially get the skeletal stem cells and then stimulate Hh signaling in adults.

“Local temporal stimulation of Hh signaling lengthens the legs.”

You can see from F how dramatically Hedgehog signaling increased the growth plate(SAG).

“The bony epiphysis (which develops from the Secondary Ossification Center) appears to be an appropriate location for such intervention, allowing placement of the Hh pathway agonist in close proximity to the epSSCs.”

” In the experiments presented here, some compound is likely released into the bloodstream, since an increase not only in femoral length, where the SAG-containing beads were placed, but also in the tibia of the same leg was observed. The arterial blood flow in extremities goes in the proximo-distal direction, and it is plausible that some levels of SAG diffuse in the same direction as the blood flow.”<-therefore the compound could be put into the blood stream without the beads for overall height!

Here’s a related article:

“Noriaki said he was surprised that the cells in the resting zone “weren’t just lazy and doing nothing, they’re very hardworking cells, they can occasionally wake up and keep making chondrocytes.””<-that is amazing that means that potentially they can form new growth plates.

“It’s been hypothesized for many years that chondrocytes at the bottom of the growth plate die, but these findings show definite evidence that they survive and continue to make bone, he said.”

Another study on this from Noriaki Ono:

A Subset of Chondrogenic Cells Provides Early Mesenchymal Progenitors in Growing Bones

“The hallmark of endochondral bone development is the presence of cartilaginous templates, in which osteoblasts and stromal cells are generated to form mineralized matrix and support bone marrow hematopoiesis. However, the ultimate source of these mesenchymal cells and the relationship between bone progenitors in fetal life and those in later life are unknown. Fate-mapping studies revealed that cells expressing cre-recombinases driven by the collagen II (Col2) promoter/enhancer and their descendants contributed to, in addition to chondrocytes, early perichondrial precursors prior to Runx2 expression and, subsequently, to a majority of osteoblasts, Cxcl12 (chemokine (C-X-C motif) ligand 12)-abundant stromal cells and bone marrow stromal/mesenchymal progenitor cells in postnatal life. Lineage-tracing experiments using a tamoxifen-inducible creER system further revealed that early postnatal cells marked by Col2-creER, as well as Sox9-creER and aggrecan (Acan)-creER, progressively contributed to multiple mesenchymal lineages and continued to provide descendants for over a year. These cells are distinct from adult mesenchymal progenitors and thus provide opportunities for regulating the explosive growth that occurs uniquely in growing mammals.”

Have to figure out what’s unique about these cells and if there is a way to make these cells reawaken

“Chondrocytes in the growth plate continue to proliferate well into adulthood in mice”

“ In the center of the developing cartilage mold, chondrocytes stop proliferating and become hypertrophic chondrocytes. These cells signal to induce the migration of mesenchymal cells into the marrow space; these cells then differentiate into osteoblasts that then form bone on top of the cartilaginous matrix. Perichondrial precursors expressing osterix (Osx) invade into the cartilage template along with blood vessels and eventually become both osteoblasts and stromal cells in the marrow space”

“growth-related mesenchymal progenitors identified here and adult mesenchymal precursors.” We have to get these back

This below study indicates that Myo-inositol can increase mandibular condylar cartilage growth but mandibular condylar cartilage can keep growing so we can’t be sure if this applies to long bones but it’s still promising. Myo-inosotol is available for purchase and it’s relatively cheap.

From WebMD “Inositol, also called myo-inositol, D-chiro-inositol, or hexaphosphate (IP6), plays a critical role in the body’s cellular growth. Though it used to be referred to as Vitamin B8, inositol is not actually a vitamin.”

Inositol is already in foods such as beans, bananas, nuts, raisins,and brown rice.

So the question is whether additional supplement is necessary and whether that additional supplementation can result in longitudinal bone growth.

Mandibular Endochondral Growth Is Specifically Augmented by Nutritional Supplementation with Myo-Inositol Even in Rabbits 

“At present, functional orthodontic appliances are used for stimulating mandibular growth in pediatric cases{bite jumping appliance also has potential to work post skeletal maturity}. However, the effectiveness of functional appliances is not always stable in daily practices. A more effective, reliable, and safer therapeutic method for mandibular growth promotion would be helpful for growing mandibular retrognathism patients. As we previously discovered that nutritional supplementation of myo-inositol in growing mice specifically increases mandibular endochondral growth{maybe it could enhance growth of other cartilage} we performed preclinical animal experiments in rabbits in this study. Briefly, six-week-old male Japanese white rabbits were fed with or without myo-inositol supplementation in laboratory chow until 25 weeks old, and 3D image analysis using micro CT data and histological examinations was done. Myo- inositol had no systemic effect, such as femur length, though myo-inositol specifically augmented the mandibular growth{so we have to investigate why that is, perhaps myo-inositol could be combined with other supplements to grow taller}. Myo-inositol increased the thickness of mandibular condylar cartilage. We discovered that the nutritional supplementation of myo-inositol during the growth period specifically augmented mandibular growth without any systemic influence, even in rabbits. Our results suggest the possibility of clinical use of myo-inositol for augmentation of the mandibular growth in growing mandibular retrognathism patients in the future.”

The fact that they think there might be clinical use is promising as it again it is available in foods so it suggests that supraphysiological doses might be helpful.

“A functional appliance is reported to induce mandibular growth by augmentation of endochondral growth in mandibular condylar cartilage and remodeling of the temporomandibular joint”<-this would be amazing if we could get it to happen in other joints and could be the key to growing taller

“nutritional supplementation of myo-inositol in growing mice specifically increases mandibular endochondral growth”<-however mice may not have as diverse a diet as humans

They suggest that mayo-inositol likely did not have systemic effect on growth as there was no change in body weight but if you look at the image you see a slight increase versus control.

However this sentence is not promising “

e myo-inositol group was 90.6 ± 1.1
group was 45.0 ± 1.5 mm, and that of the myo-inositol group was 43.4 ± 1.6 mm, and no mm. There was no statistically significant difference between the groups in femur length.
This result suggests that myo-inositol does not have any promotional effect on bone
statistically significant difference between the groups was observed. As to the femur length,
the control group was 91.3 ± 0.9 mm, and the myo-inositol group was 90.6 ± 1.1 mm.”

However the rabbits(Japanese white rabbits) were given the doses at 6 weeks old and sacrificed at 25 weeks old which is pretty young so it’s possible that growth was slowed but the growing period was elongated. Rabbits stop growing between 5-18months.

Myo inosotol significantly increased mandibular length

“discovered that Pik3cd is specifically strongly expressed in mandibular condylar cartilage”<-maybe we can increase this expression other cartilages to make them grow.

“growth augmentation of the mandible with myo-inositol requires no local injection but just simply needs to supplement the food.”

So the big takeaway here is to make sure you’re getting enough your diet but perhaps we have to find a way to upregulate Pik3cd to grow other joints.

“growth augmentation in the mandible by supplementation of myo- inositol, it was 4.7% induction in our experiments using rabbits. Our previous experiment revealed 8.4% induction in mice”

“inhibition of Pik3cd by a chemical inhibitor almost completely inhibited myo-inositol-mediated augmentation of chondrocyte proliferation in mice”

So next actions for height seekers are definitely to to see if we can increase Pik3cd in other joints to make them more like mandibular condylar cartilage.

One of the mechanisms by which Lithium may increase height is by phosphorylating Gsk 3 Beta. Lithium may also have an impact on the p38 pathway. Lithium also increased proliferation of stem cells.

This study shows directly that Lithium increases growth.

Lithium rescues cultured rat metatarsals from dexamethasone-induced growth failure

“lithium chloride (LiCl) is known to induce cell renewal in various tissues”

“After 14 days of culture, the length of dexamethasone-treated fetal rat metatarsals increased by 1.4 ± 0.2 mm compared to 2.4 ± 0.3 mm in control bones (p< 0.001). The combination of LiCl and dexamethasone led to bone length increase of 1.9 ± 0.3 mm (p< 0.001 vs. dexamethasone alone). By adding lithium, genes for cell cycle and Wnt/β-catenin, Hedgehog and Notch signaling, were upregulated compared to dexamethasone alone group.”

But they also studied Lithium on its own.

“local side-effects of GCs is the induction of apoptosis in growth plate chondrocytes,⁵through an increase in the expression of the pro-apoptotic protein Bax”<-Lithium could help reduce cellular apoptosis.

“exogenous GCs have been also shown to impair osteoblast and chondrocyte differentiation via downregulating the Wnt/β-catenin pathway, another key signaling cascade implicated in bone development and local growth plate regulation”<- we know that Lithium affects this pathway.

“Lithium chloride (LiCl) is a known GSK3β inhibitor and the treatment with LiCl increases the proliferation of human mesenchymal stem cells and also rescues from glucocorticoid-induced apoptosis of spontaneously immortalized murine calvarial osteoblasts”

“Bones treated with LiCl alone grew similarly as control (2.55 ± 0.18 mm, 2.64 ± 0.28 mm and 2.59 ± 0.33 mm increase, for 0.1 mM, 1.0 mM and 10 mM LiCl concentration, respectively; versus 2.43 ± 0.25 mm increase for control bones” so you can see that lithium increased growth versus control by about 10% versus the control group! The medium dosage grew the most so Lithium is probably biphasic(there is an optimal equilibrium dose where more has either no effect or is detrimental)

Here’s of what Lithium treated metatarsal looks like via controls:

Here’s another image that shows how significant it is:

“Lithium influenced the expression of 184 genes, of which 98 were up-regulated and 86 were down-regulated”

“a surgical osteoarthritis in vivo model, LiCl provided both in drinking water and intra-articularly was shown to improve the osteoarthritis score and to reduce the severity of cartilage destruction”

“the longitudinal bone growth setting, the results obtained from our proof-of concept experiments are supported by a previous study where lithium carbonate administration increased the width of the proximal tibia growth plate in the domestic fowl. The growth-promoting effect of LiCl was only minor in our “healthy” fetal rat metatarsals, compared to the effect in dexamethasone-impaired metatarsals”

“LiCl upregulates Axin degradation, which leads to β-catenin-induced transcriptional activity, Wnt/β-catenin pathway seems to be a plausible target that could explain the growth-promoting effect of LiCl in the dexamethasone-impaired metatarsals.”

“higher doses of LiCl have clinically been associated with undesired side effects such as tremor, dizziness, nausea, polyuria, weight gain, hypercalcemia or hypothyroidism, which therefore limits the use of high-dose LiCl treatment”<-again Lithiun is biphasic

So looks Lithium could be a height increase supplement and it is available to people!

A Wolff in sheep’s clothing: Trabecular bone adaptation in response to changes in joint loading orientation

Most loading to bones is axial but there is always some non-axial loads as the bones have shape thus there is a mix of tensile, compressive, and torsional loading. But loading bones in one axis will tend to produce the same stimuli, whereas doing things like lateral and torsional will induce unique stimuli. This will produce more effective adaptations including possibly growing taller if the loading is sufficient.

“This study tests Wolff’s law of trabecular bone adaptation by examining if induced changes in joint loading orientation cause corresponding adjustments in trabecular orientation. Two groups of sheep were exercised at a trot, 15 min/day for 34 days on an inclined (7°) or level (0°) treadmills. Incline trotting caused the sheep to extend their tarsal joints by 3–4.5° during peak loading (P b 0.01) but has no effect on carpal joint angle (P= 0.984). Additionally, tarsal joint angle in the incline group sheep were maintained more extended throughout the day using elevated platform shoes on their forelimbs. A third “sedentary group” group did not run but wore platform shoes throughout the day. As predicted by Wolff’s law, trabecular orientation in the distal tibia (tarsal joint) were more
obtuse by 2.7 to 4.3° in the incline group compared to the level group;{Can this change in trabecular orientation effect bone length?} trabecular orientation was not significantly different in the sedentary and level groups. In addition, trabecular orientations in the distal radius (carpal joint) of the sedentary, level and incline groups did not differ between groups, and were aligned almost parallel to the radius long axis, corresponding to the almost straight carpal joint angle at peak loading. Measurements of other trabecular bone parameters revealed additional responses to loading, including significantly higher bone volume fraction (BV/TV), Trabecular num-ber (Tb.N) and trabecular thickness (Tb.Th), lower trabecular spacing (Tb.Sp), and less rod-shaped trabeculae (higher structure model index, SMI) in the exercised than sedentary sheep.
Overall, these results demonstrate that trabecular bone dynamically adjusts and realigns itself in very precise relation to changes in peak loading direction{it’s also possible that mixing up axial, lateral, and torsional loading could cause the trabecular to have to constantly dynamically adjust}, indicating that Wolff’s law is not only accurate but also highly sensitive”

“changes in posture will alter stress distribution within the bone and eventually, if they persist, the trabecular structure will readjust to the new stress trajectories.”

The paper mentions that different locomotive methods induce changes in trabecular orientation.

“As intended, the angle of the tarsal joint was more extended by 3.6° at
the time of peak GRF (midstance) in the incline group”

From the looks of this image the incline group looks like it stands taller even though bone length may be the same.

“a minimum level of loading is necessary to affect trabecular growth is evident from the almost total lack of trabeculae documented in the sagittal
ridges of the distal tibia and radius”<-So there must be sufficient weight used in lateral and torsional loading regimes.

“An additional limitation is that we studied only very young animals whose joints were still growing and remodeling.”

Note how much bigger and longer the epipihysis is in image B versus A but again these are growing animals. They said that trabecular did not really change much in the radius(groups A and B) but the two radius look much bigger.

In contrast the Group D looks smaller than group C which is the tibiae which is what changed.

Studies like Trabecular bone in the calcaneus of runners, were conducted on runners above age 20 so it’s likely still that trabecular bone is responsive to the direction of loading.

The paper Physical activity engendering loads from diverse directions augments the growing skeleton, shows that again loads from diverse directions are important thus perhaps typical axial loading is enough.

“Growing mice housed for three months in cages designed to emphasize
non-linear locomotion (diverse-orientation loading) were found to have enhanced trabecular and cortical bone in the proximal humerus compared to animals housed in cages that accentuated linear locomotion (stereotypic-orientation loading).”

These papers show why we must try to use experiment with lateral and torsional loading methods in attempts to grow taller.

This study shows that mechanical loading can alter the growth plate and the trabecular bone. This shows it is possible to use mechanical loading to alter height during development and also perhaps spinal height as there is a great deal of cartilage via the discs there.

Unveiling the Trabecular Connection: Exploring Morphological Adaptations in the Growth Plate and Their Response to Mechanical Stimulus

“The growth plate, also known as the epiphyseal plate, is a critical element in the longitudinal growth of long bones during development. This study aims to explore the connection between trabecular patterns and morphological alterations within the growth plate, particularly concerning their impact on shape and mamillary processes or trabecular patterns as well as the formation of ossification bridges{ossification bridges has the potential to reduce growth so studying them has potential}. Our objective is to investigate how the adaptations in the growth plate and the trabecular bone in its vicinity respond to mechanical stimulus, this approach is considered a new methodology to study endochondral growth and bone remodelling”

“Our investigation revealed insights into the development of the growth plate and its capacity to adapt its shape in response to the local mechanical environment. Previously, this environment had been predominantly modeled as a continuum, but our model allowed us to assess the impact of localized load transmission via the trabecular groups. Furthermore, our research demonstrated that the morphological changes within the growth plate in addition to bone adaptation in its vicinity, serve as an adaptive mechanism to withstand shear stress{so we would want to optimally induce shear stress, I believe that torsional loading is the best way to induce fluid shear}, contributing to increased bone density in specific regions”

“at birth the growth plates have a flat and smooth topology in humans, as age increases a wavy pattern is seen, this change is due to mechanical stresses”

“The thickness in the growth plate remains constant during childhood thanks to an equilibrium between chondrocyte proliferation and apoptosis. In puberty, when this balance is perturbed, the process of growth plate fusion starts, forming ossification bridges in different locations until the entire plate has been ossified, leaving behind a bone remnant, formally known as epiphyseal scar”

“animals, such as mice and rats, which are widely used as in-vivo models for endochondral ossification studies, do not entirely close their growth plates during maturation”<-but their growth plates do seem to be become senescent which indicates that there may be epigenetic factors that limit growth plates from growing indefinitely.

“the change in shape in the growth may occur as a consequence of the bone remodeling process in the vicinity of the growth plate, and at the same time trabecular formations adapt”