Monthly Archives: February 2015

Interesting Review Paper on Bone Growth

Factors affecting bone growth

“Longitudinal bone growth depends on the growth plate{although some other regions may contribute in a minor way}. The growth plate has 5 different zones—each with a different functional role—and is the final target organ for longitudinal growth. Bone length is affected by several systemic, local, and mechanical factors. All these regulation systems control the final length of bones in a complicated way. ”

“Bone growth in width is also controlled by genetic factors, but mechanical loading regulates periosteal apposition”<-periosteal stem cells have the potential to differentiate into chondrocytes so it would be possible to use the mechanical loading to induce new longitudinal bone growth.

“Differences in bone size are established early in life, before puberty and perhaps even in utero. Bone begins to form when mesenchymal cells form condensations—clusters of cells that adhere through expression of adhesion molecules”

“Two models for control of bone growth in width have been suggested—the mechanostat theory (mechanical requirements regulate periosteal apposition) and the sizostat hypothesis (a master gene or set of genes regulates bone growth in width so bone reaches a preprogrammed size, independent of mechanical requirements)”

“The growth plate consists mainly of collagen fibrils, proteoglycans, and water, arranged to form a sort of sponge with very small pores. The growth plate is located between epiphyseal and metaphyseal bone at the distal end of long bones and is strain-rate–dependent, which means it is hard when squeezed rapidly but soft when deformed slowly{the means that the frequency to which stimuli is applied to the growth plate can result in a large variation in response}. The growth plate becomes ossified after puberty and epiphyseal fusion.”

“Histologically, the growth plate consists of horizontal zones of chondrocytes at different stages of differentiation. The germinal zone, at the epiphyseal end of the growth plate, contains resting chondrocytes, which seem crucial in orienting the underlying columns of chondrocytes and, therefore, in unidirectional bone growth, probably by secretion of a growth plate–orienting factor. Next is the proliferative zone, a matrix-rich zone in which flattened chondrocytes undergo longitudinal cell division and orient themselves in typical column-wise fashion. At some point, proliferating chondrocytes lose their capacity to divide; they start to differentiate and become prehypertrophic, coinciding with a size increase. Proliferating chondrocytes are located in the transition (maturation or prehypertrophic) zone. In the hypertrophic zone, round chondrocytes secrete matrix proteins in large amounts. This stage is characterized by an increase in intracellular calcium concentration, which is essential in the production of matrix vesicles. These vesicles, small membrane-enclosed particles, are released from chondrocytes and secrete calcium phosphates, hydroxyapatite, and matrix metalloproteinases, resulting in mineralization of the vesicles and their surrounding matrix. The chondrocytes in this mineralized zone eventually undergo programmed cell death (apoptosis), leaving a scaffold for new bone formation. ”

“Generally, bones increase in length as long as new material is being squeezed between the reserve zone of the growth plate and the zone of provisional calcification.”<-Can we still do this post epiphyseal fusion?

“Intracellular calcium concentration increases in the hypertrophic chondrocytes in the hypertrophic zone of growth plate cartilage; at some point, these chondrocytes begin to mineralize the longitudinal septa in the surrounding matri. At the growth cartilage junction, mononuclear cells of undetermined origin resorb the unmineralized horizontal septa of the growth cartilage. These cells are called septoclasts or chondroclasts. Blood vessels invade the area and pave the way for bone cell precursors. Eighty percent of the longitudinal septa of the growth cartilage is rapidly resorbed in the metaphyseal zone immediately behind the invading blood vessels, paving the way for bone cell precursors. About 40% of mineralized septa serves as scaffold for the formation of primary bone trabeculae; the other 60% is absorbed by chondroclasts (osteoclasts) near the vascular invasion front. ”

The scientists list factors that positively influence bone growth:

I think to or after a certain level should be applied to almost all of these like Estrogen.  This list shouldn’t be taken as gospel as there is a lot more detail in how these hormone influence longitudinal bone growth.  Innervation is to supply a body part with nerves and I think too has a more complex relationship to longitudinal bone growth than is alluded too.

“GH acts on resting zone chondrocytes and is responsible for local IGF-1 production, which stimulates clonal expansion of proliferating chondrocytes in an autocrine/paracrine manner. Infusion of GH or IGF-1 shortens stem- and proliferating-cell cycle times in the growth plate of hypophysectomized rats and decreases the duration of the hypertrophic differentiation phase, with GH being more effective. According to [an] experimental study, GH or IGF-1 treatment restores mean cell volume and height, but the growth rate is not normalized by either hormone. ”

“hyperthyroidism increases the growth rate in children but also leads to premature growth plate fusion and short stature. T3 seems to stimulate recruitment of cells from the germinal zone to the proliferating zone and facilitates differentiation of growth plate chondrocytes. Its precursor, T4, increases the number of [3H]methylthymidine-labeled chondrocyte nuclei and [35S]incorporation in Snell dwarf mice growth plates, suggesting a stimulatory role in chondrocyte proliferation and differentiation”

However, I think this view overemphasizes the importance of hormones.  You can read more on hormones in the full study which I provided a link too in the top.

“If compression always inhibited bone growth, as it was believed, growth plates would be extremely unstable, as any slight deviation from the straight alignment of the long bones of the lower extremities would induce a vicious circle of positive feedback and result in catastrophic deformities. Mild compression leads to increased, not decreased, growth. Nevertheless, when compression on one side of the growth plate exceeds a certain level, growth is indeed suppressed, and the lesion begins to worsen.”

Hypothesized theory of input of compression and tension on growth rate.

“bone cells accommodate to a customary mechanical loading environment, making them less responsive to routine loading signals”

“muscle pull affects periosteal tension and, consequently, bone form and growth in length”

“wider bones must have higher midshaft periosteal apposition rates, as this is how they
become wider.”

New info about reversing growth plate ossification: chondrocyte transdifferentiation into osteoblasts

I found earlier studies about chondrocyte transdifferentiation into osteoblast such as this.

Essentially, what’s so significant about chondrocyte transdifferentiation into osteoblasts is that it means that the growth plate genetics are maintained in the transdifferentiated-from-chondrocytes osteoblasts.  So if we can induce de-differentiation of these transgene osteoblasts then we can possibly form neo-growth plates.  This is a much more promising for height growth than the view where hypertrophic chondrocytes just undergo apoptosis and no growth plate genetic information would be maintained by apoptosis whereas if hypertrophic chondrocyes transdifferentiate into osteoblasts some of the growth plate genetic information would be maintained info the former-hypertrophic chondrocytes osteoblasts.

Chondrocytes Transdifferentiate into Osteoblasts in Endochondral Bone during Development, Postnatal Growth and Fracture Healing in Mice.

“To investigate whether cells derived from hypertrophic chondrocytes contribute to the osteoblast pool in trabecular bones, we genetically labeled either hypertrophic chondrocytes by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using EGFP, LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. These in vivo experiments allowed us to follow the fate of cells labeled in Col10a1-Cre or Agc1-CreERT2 -expressing chondrocytes. After the labeling of chondrocytes, both during prenatal development and after birth, abundant labeled non-chondrocytic cells were present in the primary spongiosa. These cells were distributed throughout trabeculae surfaces and later were present in the endosteum, and embedded within the bone matrix. Co-expression studies using osteoblast markers indicated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts{maybe we could investigate these other non-osteoblastic chondrocyte derived cells if they can be used for height increase purposes?}. Both chondrocytes prior to initial ossification and growth plate chondrocytes before or after birth have the capacity to undergo transdifferentiation to become osteoblasts. The osteoblasts derived from Col10a1-expressing hypertrophic chondrocytes represent about sixty percent of all mature osteoblasts in endochondral bones of one month old mice{this is a significant proportion which gives a lot of promise about reversing endochondral ossification}. A similar process of chondrocyte to osteoblast transdifferentiation was involved during bone fracture healing in adult mice. In addition to cells in the periosteum, chondrocytes represent a major source of osteoblasts contributing to endochondral bone formation in vivo. ”

I’d recommend visiting the study as there were some images I couldn’t get onto here.

“Endochondral bone is made of an outer compact bone (cortex) and an inner spongy bone tissue within the bone marrow cavity. The conversion from the nonvascular cartilage template to fully mineralized endochondral bones proceeds in distinct and closely coupled steps. The first step is initiated when chondrocytes in the center of the cartilage models undergo hypertrophic differentiation and cells in the perichondrium surrounding the hypertrophic zone differentiate into osteoblasts to form the interim bone cortex (bone collar). Concurrently, the initial vascular invasion occurs in the same region importing blood vessel-associated pericytes, osteoclasts and progenitor cells in the circulating blood”

“Immediately following the onset of bone collar formation, hypertrophic chondrocytes and the mineralized cartilage matrix in the center of the cartilage template are replaced by a highly vascularized trabecular bone tissue as well as bone marrow. Bone trabeculae in the primary spongiosa are formed by deposition of osteoid by osteoblasts on the surface of calcified cartilage spicules.”

“During endochondral ossification, terminally differentiated hypertrophic chondrocytes are eventually completely removed from the initial cartilage template or growth plates. Some of these chondrocytes have been shown to be eliminated through either apoptosis or autophagy (type II programmed cell death). Hypertrophic chondrocytes express osteoblast markers, such as Alkaline Phosphatase (ALPL), Osteonectin (SPARC), Osteocalcin (BGLAP), Osteopontin (SPP1) and Bone sialoprotein (IBSP), implicating potential complex functions of these cell”

in cell cultures containing ascorbic acid or in organ cultures, hypertrophic chondrocytes, instead of becoming extinct, resume cell proliferation and undergo asymmetric cell division, giving rise to cells with morphological and phenotypic characteristics of osteoblasts capable of producing a mineralized bone matrix in vitro“<-Could this be a perpetual growth plate?

“in embryonic chicks, long bone chondrocytes differentiated to bone-forming cells and deposited bone matrix inside their lacunae”

“After the growth period the Col10a1-Cre induced reporter+ cells were still present in the metaphyseal and cortical regions in 6-month-old mice”<-6-month old mice are pretty old and not really growing based on the breed of mice so this is promising that the transChondro-Osteoblasts could still be around in older humans.

“However, more of these cells were embedded within the bone matrix, and less of them were found on the bone surfaces, compared to the 2- and 3-week-old mice, implying that the number of active osteoblasts derived from chondrocytes was likely reduced after the growth period. At 8-month, there were almost no Col10a1-Cre induced reporter+ cells in the primary spongiosa and very few were on the bone surfaces.”<-This is less promising information.  TransChondro-Osteoblasts on bone surfaces are in a better position to form neo-growth plates.

“Hypertrophic chondrocytes might first dedifferentiate, then proliferate before these cells redifferentiate into osteoblasts. The existence of cells in the bone marrow that were derived from Col10a1-expressing chondrocytes. These cells displayed properties of mesenchymal progenitor cells and were able to differentiate into osteoblasts, chondrocytes and adipocytes in vitro, although we do not know whether these cells had the ability to become osteoblast cells in vivo. “hypertrophic chondrocytes to osteoblasts” transdifferentiation may indeed involve a dedifferentiation and then a redifferentiation process. In juvenile mice the chondrocyte-derived reporter+ cells, which were negative for osteoblast markers, persisted in the primary spongiosa for a considerable amount of time before becoming functional osteoblasts”<-This information doesn’t really hurt the prospects of using the genetic information of these cells to create new growth plates as even if there’s a dedifferentiation stage between chondrocytes becoming osteoblasts the genetic material will still be maintained.

According to Buried alive: How osteoblasts become osteocytes, ” the average half-life of a human osteocyte as 25 years. However, when we consider an overall bone-remodelling rate of between 4 to 10% per year, the life of many osteocytes may be shorter. Furthermore, the lifespan of osteocytes greatly exceeds that of active osteoblasts, which is estimated to be only three months in human bones”<-So we’d only have three months after growth plate fusion to induce dedifferentiation of trans-chondro osteoblasts before they don’t exist anymore.  10-20% of osteoblasts become osteocytes and osteocytes live longer but osteocytes are in a much less advantageous position to form new growth plates.

Here’s a study that mentions alternative theories:

Pubertal growth and epiphyseal fusion

“There are four theories on the cellular mechanism of epiphyseal fusion after the pubertal growth spurt. Apoptosis, autophagy, hypoxia, and transdifferentiation have been considered the causes of epiphyseal fusion”

Apoptosis: “Hypertrophic chondrocytes of the growth plate undergo death by apoptosis, leaving behind a frame of cartilage matrix for osteoblasts that invade and lay down bone.”

Autophagy: “Autophagy is another method of programmed cell death that involves a catabolic process in which the cell degrades its own components through autophagosomes. ”

Hypoxia: “a dense border of thick bone surrounding growth plate remnants [is present] in a human growth plate tissue specimen undergoing epiphyseal fusion.  The dense border might act as a physical barrier preventing oxygen and nutrients from reaching the fusing growth plate, resulting in hypoxia and eventually cell death in a nonclassical apoptotic manner.”

Transdifferentiation: “terminal hypertrophic chondrocytes transdifferentiate into osteoblasts at the chondroosseous junction of the growth plate”

Scientists find a significant increase in height due to heat application

It’s long been noticed that heat can increase longitudinal bone growth but mostly there has been a lack of concrete numbers.  It may have little impact on adult height growth due to mostly impacting the growth plate however heat may have an impact on stem cells.

Unilateral Heat Accelerates Bone Elongation and Lengthens Extremities of Growing Mice

“Current bone lengthening protocols involve invasive surgeries or drug regimens, which are only partially effective. Exposure to warm ambient temperature during growth increases limb length, suggesting that targeted heat could noninvasively enhance bone elongation. Daily heat exposure on one side of the body unilaterally increases femoral and tibial lengths. Mice (N = 20) were treated with 40C unilateral[only one side of the body] heat for 40 minutes/day for 14 days post-weaning[after no longer taking breast milk]. Non-treated mice(N = 6) served as controls. Unilateral increases in ear (8.8%), hindfoot (3.5%), femoral (1.3%) and tibial(1.5%) lengths were obtained.Tibial elongation rate was >12% greater (15 µm/day) on the heat-treated side.Extremity lengthening correlated with temperature during treatment. Body mass and humeral length{It’s interesting that heat only worked for certain bones} were unaffected. To test whether differences persisted in adults, mice were examined 7-weeks post-treatment. Ear area, hindfoot, femoral, and tibial lengths were still significantly increased ∼6%, 3.5%, 1%, and 1%, respectively, on the heat-treated side{So the heat treatment permanently increased growth and not just growth rate.  That ear area increased shows that the cartilage itself is affected}. Left-right differences were absent in non-treated controls, ruling out inherent side asymmetry. This model is important for designing noninvasive heat-based therapies to potentially combat a range of debilitating growth impediments in children.”

Here’s a rodent skeleton:

mouse skeleton

Let’s say your tibia and femur together are about 30 inches.  A one percent increase would be about .3inches resulting in a 3rd of an inch increase in height.  Since the heat applied is not optimized there’s the possibility for more.

“A major obstacle to successful bone lengthening by noninvasive means is difficulty in targeting therapeutics to cartilaginous growth plates, which do not have a direct blood supply{Note that LSJL is able to target the growth plates and the stem cells within the growth plates via mechanical loading}. Experimental drug delivery approaches include surgically implanted catheters and localized injections into specific growth plates”<-Note that Ping Zhang was able to stimulate length growth without injecting directly into the growth plate via localized IGF2 injections.

“Data from our lab and others demonstrate that exposure to warm ambient temperature
during growth increases bone blood supply and length in young mice.”<-The increase in bone blood supply could have an impact in adults as well if the right stimuli was in place to induce the formation of new growth plates.

“intermittent targeted heating could be accomplished with a heating pad or temperature cuff.”

Here’s an adjustable heating pad.  I haven’t testing it myself and I’m not sure if it’s the best one but it is a sample:

 

“goal is to develop a low-cost, noninvasive method for lengthening bones that can translate
into practical therapy to offset linear growth impediments in children.”<-They believe that heat can work in human children to increase growth.

“Mice were anesthetized with 1.5% isoflurane and placed in lateral recumbency on a
40C heating pad for 40 minutes each day”

“The 3-5 week age interval is a time of rapid, temperature-sensitive growth in mice. By comparison, this period could be considered roughly similar to human development between toddler age and entry to middle school.”

“Limbs on the heat-treated side were wrapped in custom fitting thermal booties to ensure uniform heat distribution”

“In addition to limb length, cartilaginous ears were measured to document a treatment effect because ear size increases with ambient temperature”

“Skin temperatures of heat-treated hindfeet and ears averaged 40C during treatments. Nontreated side temperatures averaged 30C with no major fluctuations”<-So 10C of heat increase resulted in a 1% increase in leg length.  It’s unclear whether more heat would result in more lengthening.

“When nontreated and heat-treated sides were analyzed in aggregate, there were significant positive correlations between hindlimb temperature and tibial elongation rate”

“short-term (30-minute) hindlimb heating increases molecular uptake in mouse tibial growth plates”<-this doesn’t really help adults create neo-growth plates.

“Although it is unclear why humeral length did not differ, one potential explanation is the warmer starting temperature of the forelimb when compared to the hindlimb. The knee joint capsule is normally at least 3-4C lower than body core.Our treatments elevated hindlimb temperature by 10C on the heat-treated side.
However, skin temperatures in the humeral region more closely resembled body core, consistent with thermal maps for humans showing that 37C core temperature extends into the shoulder region, while extremity temperatures progressively decrease in a proximal-distal gradient.”

“Our working hypothesis is that heat-treatments do not impact temperature of the humerus
due to the proximity of this joint to the body core, and the disproportionately large volume of
warm blood delivered to the shoulder region through the large subscapular artery”

“the left-right symmetry in humeral length reflects its relatively constant temperature. This could be tested by decreasing shoulder temperature with cold, which stunts limb elongation in a dose-dependent manner”

“up to a 20% increase in bone growth rate for every one degree C increase in incubation temperature in growing chicks.”

“unilateral exposure of mild, non-damaging 40C heat for 40-minutes per day for only 14 days permanently increased ear area and hindlimb length on heat-treated sides of young mice.”

“the width of the mouse growth plate is only a fraction of that of a human growth plate. It will be important to replicate these results in a larger animal model to ensure that heat can fully penetrate a larger growth plate, so as to avoid potential angular growth deformities. This should not be problematic, however, sincewhole body heat-effects on bone length have already been demonstrated in experiments using large animals”

I already feel a bit of a temperature elevation when performing LSJL.

According to Periodic heat shock accelerated the chondrogenic differentiation of human mesenchymal stem cells in pellet culture., Heat increased chondrogenic differentiation although they were cells already committed to the chondrogenic lineage.  41C for 1 hour was the stimulus used.

Grant promises to use heat to increase longitudinal bone growth

This project has a decent amount of funding(over 300K).

Heat enhanced molecular delivery to growth plates for targeted bone lengthening

“Linear growth deficiencies have multiple etiologies, ranging from injury and illness to genetic bone disease. Bone elongation disorders are particularly challenging to treat because of the relative inability to regulate molecular delivery o the growing skeleton. The primary obstacle to successful clinical intervention is lack of molecular delivery to the growing skeleton. The primary obstacle to successful clinical intervention is lack of methods for targeting therapeutics to growth plate cartilage, which does not have a penetrating blood supply. Existing procedures for limb lengthening involve invasive surgery or drug regimens, which are to date only partially effective. Data generated by the applicant show that localized heating increases molecular uptake in growth plate cartilage in vivo, suggesting that heat could be a noninvasive and inexpensive alternative for augmenting delivery of bone-lengthening drugs. The long-term goal is to identify physiological mechanisms underlying temperature-enhanced bone elongation in the growth plate{is this a method just to increase drug delivery or is the temperature alone a driving factor in elongation?}. The overall objective of the problem-solving proposal is to determine whether heat augments the bone-lengthening effects of systemic growth regulators. Insulin-like growth factor (IGF)-I is a potent stimulator of linear growth and part of a drug regimen used in children. The central hypothesis, based on strong preliminary data and tested under two specific aims using dynamic in vivo multiphoton microscopy, is that heat localizes delivery of systemic IGF-I into growth plates to promote additive bone lengthening{so this implies that the heat increases delivery of IGF-1 already in the body to the growth plates}.
Specific Aim 1 uses in vivo cartilage imaging to determine dose, timing, and temperatures that maximize IGF-I uptake in 5-week-old mouse tibial growth plates. Injections of fluorescently labeled IGF-I and size proxy tracers will be given to quantify molecular uptake and clearance in the growth plate. Real time imaging will be used to determine delivery rate and total volume of labeled molecules in the growth plate and surrounding vasculature after timed injections. Permeability of the vessels and matrix will be measured at different doses and temperatures.
Specific Aim 2 uses a novel limb heating model to determine if heat-enhanced IGF-I uptake in growth plates causes unilateral limb lengthening, analyzed by quantifying growth rate and biomarkers of IGF-I activation in heat-treatable tibiae. Injections of IGF-I and its receptor antagonist will explicitly show if heat-enhanced uptake increases bone length. IGF-I deficient growth hormone receptor knockout mice will be used to test the drug-targeting efficacy of heat in a disease model. The rationale is to facilitate design of heat based drug-targeting approaches to enhance length at specific skeletal sites using noninvasive techniques. This project is innovative by using multiphoton imaging to assess growth plate physiology at the cellular level in vivo, in a dynamic way not possible with other methodologies. This contribution is significant because it can yield transformative findings that mechanistically link heat, bone lengthening, and vascular access to growth plates. Such results could fundamentally shift the approach that physicians take in treating a spectrum of growth plate disorders, leading to new therapies with better outcomes by reducing amount, toxicity and costs of high-dose systemic pharmaceuticals. ”

What’s also interesting is that when I perform LSJL I can feel the temperature of my bones increasing slightly.  Although to recreate a growth plate would require more than just IGF-1.

H3K4 may be involved in growth plate cessation

This grant by Jeffrey Baron has insights on the cessation of growth.

Regulation Of Childhood Growth

“Children grow taller because their bones get longer. This bone elongation occurs at the growth plate, a thin layer of cartilage within juvenile bones. The growth plate contains progenitor cells located within the resting zone. Children stop growing taller because the growth plate cartilage undergoes programmed senescence which involves extensive changes in gene expression, declining chonodrocyte proliferation, altered chonodrocyte differentiation, and involution of the growth plate{Note that this does not necessarily involve estrogen although estrogen may be a part of it}. Eventually growth plate senescence leads to cessation of bone elongation and epiphyseal fusion. Estrogen accelerates this developmental process, causing growth to stop earlier.  Senescence occurs because progenitor cells in the resting zone of the growth plate are depleted in number and that estrogen acts by accelerating this depletion. Body size varies enormously among mammalian species. In small mammals, body growth is typically suppressed rapidly, within weeks, whereas in large mammals, growth is suppressed slowly, over years, allowing for a greater adult size. Body growth suppression in rodents is caused in part by a juvenile genetic program that occurs in multiple tissues simultaneously and involves the downregulation of a large set of growth-promoting genes{If we can upregulate these genes via mechanical and dietary mechanisms can we reverse this body growth surpression?}. This genetic program is conserved among mammalian species but that its time course is evolutionarily modulated such that, in large mammals, it plays out more slowly, allowing for more prolonged growth and therefore greater body size. Epigenetic mechanisms may orchestrate this juvenile growth-regulating genetic program. Extensive genome-wide shifts in H3K4 and H3K27 histone methylation [occur] with age. Temporal changes in H3K4 trimethylation showed a strong, positive association with changes in gene expression whereas changes in H3K27 trimethylation showed a negative association. Genes with decreases in H3K4 trimethylation with age were strongly implicated in cell cycle and cell proliferation functions. The common core developmental program of gene expression which occurs in multiple organs during juvenile life is associated with a common core developmental program of histone methylation. In particular, declining H3K4 trimethylation is strongly associated with gene downregulation and occurs in the promoter regions of many growth-regulating genes, suggesting that this change in histone methylation may contribute to the component of the genetic program that drives juvenile body growth deceleration. In some children with subnormal linear growth, a cause can be identified, but in many the etiology remains unknown. This condition, idiopathic short stature (ISS), can sometimes be severe. We used whole-exome sequencing to study three families with autosomal dominant short stature, advanced bone age, and premature growth cessation. In these families, we identified novel heterozygous mutations in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. Our study demonstrated that heterozygous mutations in ACAN can cause a skeletal dysplasia which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the child who presents with short stature and accelerated skeletal maturation. ”

So we want to study H3K4 trimethylation and see if we can re-upregulate it during aging to find away to grow taller.  Although he only claims that H3K4 trimethylation downregulation is only associated with gene downregulation, he suggests that this H3K4 trimethylation downregulation may be a part of a larger program to cease growth.

Although it seems like it would be very difficult to manipulate H3K4 trimethylation and it would require something like a retrovirus.