New LSJL study was published that has some good stuff.  Maybe the paper will finally give the insight on how to use mechanical loading to gain height.

Loading-driven PI3K/Akt signaling and erythropoiesis enhanced angiogenesis and osteogenesis in a postmenopausal osteoporosis mouse model

“Bone vasculature influences osteogenesis[any type of new bone formation and haematopoiesis[production of blood cells in the bone marrow] in the bone microenviroment. Mechanical loading has been shown to stimulate the formation of osteogenesis-related type H vessels in an ovariectomy (OVX)- induced osteoporosis mouse model. To determine the loading-driven mechanism of angiogenesis and the formation of type H vessels in bone, we evaluated the roles of PI3K/Akt signaling and erythropoiesis in the bone marrow. The daily application of mechanical loading (1 N at 5 Hz for 6 min/day) for 2 weeks on OVX mice inhibited osteoclast activity{although osteoclast activity is good for our purposes as degradation of bone is needed to theoretically create a new growth plate}, associated with an increase in the number of osteoblasts and trabecular volume ratio. Mechanical loading enhanced bone vasculature and vessel formation, as well as PI3K/Akt phosphorylation[Akt phosphorylation indicates general anabolism] and erythropoiesis[production of red bood clells] in the bone marrow. Notably, LY294002, an inhibitor of PI3K signaling, blocked the tube formation by endothelial progenitor cells, as well as their migration and wound healing. The conditioned medium, derived from erythroblasts, also promoted the function of HUVECs with elevated levels of VEGF, CD31, and Emcn. Collectively, this study demonstrates that mechanical loading prevents osteoporotic bone loss by promoting angiogenesis and type H vessel formation. This load-driven preventing effect is in part mediated by PI3K/Akt signaling and erythropoiesis in the bone marrow”

“A specific vessel subtype called a type H vessel, which is positive for CD31 and endomucin (CD31hiEmcnhi), has been reported to link angiogenesis with osteogenesis”

“Vascular-forming endothelial cells provide a framework of bone homeostasis and metabolism, acting as a cellular highway for blood cells, leukocytes, and other types of cells throughout the body ”

“Erythropoiesis is characterized by the movement of lineage-committed cells with progenitors, precursors, and mature red blood cell (RBC) compartments, which are located in the fetal liver and the postnatal bone marrow”

“Molecular signals by mechanosensing and transduction, leading to a series of cellular responses. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway has been shown to play a critical role in the regulation of diverse cellular functions and is also involved in angiogenesis and erythropoiesis. joint loading increases the expression of Akt, which may promote bone formation and homeostasis. The effect of PI3K signaling on endothelial progenitor cells (EPCs) in the bone marrow of OVX mice, however, has not yet been demonstrated in response to joint loading. ”

“we hypothesized that the reduction in type H vessels and the hematopoietic function in OVX mice is suppressed by mechanical loading through PI3K/Akt signaling, which stimulates erythroid differentiation of hematopoietic stem cells (HSC) and promotes vessel formation”<-so joint loading may not suppress osteoclast activity in normal bone as the OVX environment is different.

“Ninety female C57BL/6 mice (~16 weeks of age, Animal Center of Academy of Military Medical Sciences, China) were used. Mice were randomly divided into three groups: the sham control group (Sham, n = 30), the ovariectomized group (OVX, n = 30), and the loading-treated ovariectomized group (OVXL, n = 30).”<-unfortunately no loaded control group.

Above is histological slides.  Can’t really see anything abnormal.  There may be something atypical going on in F where the added arrow is pointing.

According to figure 2G PI3K, AKT, and VEGF activity was greatly enhanced by joint loading even over controls.  But according to 2H, I, J it did not increase the ratios of phosphorylated PI3K and AKT to total PI3K and AKT and VEGF relative to Beta-Actin.

“The formation of type H vessels was correlated to the stimulation of osteogenesis, and the result suggests that the promotion of type H formation and angiogenesis are important in response to load-driven suppression of OVX-induced bone loss. ”

“knee loading stimulated PI3K/Akt phosphorylation in the bone, and this stimulation can be linked to loading-driven bone metabolism”<-although this alone is definitely not sufficient to induce new longitudinal bone growth.

“Knee loading enhanced cell migration and wound healing”

“in OVX mice, load-driven angiogenesis via erythropoiesis contributed to suppressing the loss of osteoporotic bone. “<-erythropoiesis is the creation of new red blood cells.  Erythropoiesis is thought to not typically occur in adult bones so if joint loading can induce new erythropoiesis that is a big deal.

The mice here were subjected to 1n loading at 5Hz for 6 min/day.  This is actually higher than that performed on the original bone lengthening LSJL study 5-min bouts at 0.5 N[at 5Hz).

Here’s a graphical representation in the study at how mechanical loading might stimulate bone:

The estimated increase in type H vessels is dramatic.  Osteoclast activity as depicted is way done too.

And here’s the description of type H vessels “Type H vessels are noted most abundantly in young, growing animals, adjacent to the growth plate. The elongation of long bones by the process of endochondral ossification occurs at the growth plate and involves continuous replacement of cartilage matrix by calcified bone to acquire their typical shapes through bone modeling.”

Could type H vessels be the key for new longitudinal bone growth here’s a study explaining type H vessels.

Type H blood vessels in bone modeling and remodeling

“In the mammalian skeletal system, osteogenesis and angiogenesis are intimately linked during bone growth and regeneration in bone modeling and during bone homeostasis in bone remodeling. Recent studies have expanded our knowledge about the molecular and cellular mechanisms responsible for coupling angiogenesis and bone formation. Type H vessels, termed such because of high expression of Endomucin (Emcn) and CD31, have recently been identified and have the ability to induce bone formation. Factors including platelet-derived growth factor type BB (PDGF-BB), slit guidance ligand 3 (SLIT3), hypoxia-inducible factor 1-alpha (HIF-1α), Notch, and vascular endothelial growth factor (VEGF) are involved in the coupling of angiogenesis and osteogenesis.”

“in bone modeling associated with endochondral ossification, hypertrophic chondrocytes express high levels of vascular endothelial growth factor (VEGF), which promotes the vascular invasion of cartilage, recruits chondroclasts to resorb hypertrophic cartilage and osteoblasts to build the bone matrix”

“In bone modeling in response to mechanical loading, macrophage/non-resorbing osteoclast lineage cells secrete platelet-derived growth factor type BB (PDGF-BB) to recruit both endothelial and osteoblast precursor cells to couple angiogenesis with osteogenesis”

“activation of mechanistic target of rapamycin complex (mTORC) in articular chondrocytes promoted VEGF secretion into subchondral bone and stimulated type H vessel formation.”

“type H vessels were reported to digest the cartilage matrix, which may be another mechanism of cartilage degeneration in OA.”

“In fracture healing, type H vessels appear during the stage of fibrocartilaginous callus formation. Type H vessels form in the fracture callus and induce bone formation. Factors, such as SLIT3, can promote fracture healing by augmentation of type H vessel induced osteogenesis.”<-Limb lengthening basically if LSJL can induce type H vessels and if type H vessels are important in neocartilage formation than that would be a big find.  But I can only find that Type H vessels are important in absorbing the cartilage matrix not in creating the cartilage matrix.  Although increased Type H Vessels as shown in this study could be indicative of enhanced and maybe even new growth plate activity would would be massive.  IF the mice got new Type H blood vessels past skeletal maturity that would be a huge find 16 week of the type used in this study are pretty far along skeletal wise so new type H vessels is still a big deal but they are still not quite old enough.

Here’s the supplementary data attached

This for the sham and the joint loaded control no osteoarthritis.  The bones look significantly different too me with the loaded bone significantly bigger and and maybe slightly longer(hard to tell). I’d say the width difference is striking and huge. The growth plate is clearly open.  Bone parameters are bigger in the loaded group despite not being “statistically significant”.

4-Phenylbutyric acid (4-PBA, Benzenebutyric acid) is a histone deacetylase (HDAC) inhibitor and a key epigenetic inducer of anti-HCV hepatic hepcidin.  Here’s some stuff on histones.   MOre on histones.  “HDAC4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation by interacting with and inhibiting the activity of Runx2”  It’s possible since histone inhibition does enhance differentiation it may increase adult height.  But it also make differentiation happen sooner thus reducing adult height.  So there’d need to be experimentation done to see whether this makes children grow faster but reduces overall growth plate growth or whether it it makes children faster and increases overall growth plate based growth.

A compound called tubacin could also increase height by histone HDAC6 inhibition.  There’s still no over the counter tubacin.

4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts

“Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice{so we don’t know if this will help in normal people}. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI.”

This would have to be tested on normal mice to see if it works.

Evolution and future of growth plate therapeutics

“Longitudinal bone growth is regulated by multiple endocrine signals (e.g. growth hormone, insulinlike growth factor I, estrogen, androgen) and local factors (e.g. fibroblast growth factors and their receptors and the C-natriuretic peptide/NPR-2 pathway).”

“The resting zone chondrocytes, farthest from the primary ossification center, replicate at a slow rate and act as stem-like cells that replenish the pool of proliferative chondrocytes{if we can reintroduce these resting zone chondrocytes we may be able to reopen the growth plate}. Resting zone chondrocytes produce a ‘growth plate-orienting factor’ that instructs the proper spatial orientation of adjacent proliferative chondrocytes. As cells within the resting zone divide, the proliferative zone is formed in which chondrocytes replicate at a high rate, become arranged into columns, and contribute to bone elongation. Hypertrophic chondrocytes generated from terminal differentiation of proliferating zone chondrocytes enlarge in columns parallel to the axis of elongation. Cell swelling during chondrocyte hypertrophy enables chondrocytes within the growth plate to enlarge rapidly. This phase of endochondral ossification, during which chondrocytes increase their height about 6- to 10-fold, serves as the major factor regulating the growth rate amongst endochondral bones. Hypertrophic chondrocytes calcify surrounding extracellular matrix and produce factors that attract bone cell precursors, bone cells and blood vessel growth, and undergo apoptosis shortly before the blood vessels invade the chondrocyte lacuna. The overall effect of this process of chondrocyte proliferation, hypertrophy, and extracellular matrix secretion is elongation of bones and progressive creation of new bone tissue at the bottom of the growth plate. With age, the rate of longitudinal bone growth declines, caused primarily by a decrease in chondrocyte proliferation associated with other hormone-independent structural, functional, and molecular changes termed growth plate senescence. Evidence suggests that growth plate senescence occurs because the progenitor chondrocytes in the resting zone have a limited replicative capacity – gradually exhausted with increasing cell division{things like estrogen and FGFR3 may contribute to reducing the replicative capacity}.  When the proliferative capacity of stem-like cells in the resting zone is exhausted, and in the presence of sex hormones, growth plate cartilage becomes completely replaced by bone, an event termed epiphyseal fusion”

” According to the dual-effector hypothesis, GH promotes recruitment of resting chondrocytes into a proliferative state and stimulates local production of IGF-I, which then acts in a paracrine/autocrine fashion to increase chondrogenesis. The IGF-I signaling pathway plays an important role in promoting complete hypertrophic chondrocyte formation. These effects are predominantly due to growth plate-generated IGF-I, and IGF-I deficiency results in pre- and post-natal growth retardation marked in the growth plate by disorganized columnar chondrocytes, decreased cell proliferation and cell hypertrophy, increased apoptosis, and delayed vascular invasion. ”

“Estrogen influences longitudinal growth primarily and indirectly by augmenting GH secretion during puberty, but also through both growth-enhancing and -attenuating direct actions on the growth plate. A direct effect of estrogen is to advance growth plate senescence causing proliferative exhaustion, and thus epiphyseal fusion. An important mediator of this growth plate closure process is vascular endothelial growth factor (VEGF), the production of which is stimulated by estrogen in both males and females. Androgens stimulate linear growth partly due to aromatization to estrogens within growth plate cartilage, but also by direct interaction with androgen receptors on growth plate chondrocytes – explaining the GH- and IGF-I-independent growth stimulating effects of non-aromatizable compounds such as dihydrotestosterone and oxandrolone. Linear growth is slowed by deficiency of and accelerated by excess thyroid hormone. Hypothyroidism indirectly impedes linear growth by diminishing GH secretion and IGF-I, but also by decreasing chondrocyte proliferation and hypertrophy, slowing of vascular/bone cell invasion, and disruption of column organization. Glucocorticoid (GC) excess slows longitudinal bone growth by inhibiting chondrocyte proliferation, hypertrophy, and cartilage matrix synthesis. Diminished GH secretion and/or altered IGF-I bioavailability have been described in some GCtreated patients. Slowing of growth plate senescence due to GC appears to explain the phenomenon of catch-up growth following transient GC exposure and hypothyroidism.”

“Members of the FGF family of receptors (FGFRs) and their ligands are required for proper chondrocyte function, endochondral ossification and overall skeletal development. Proliferative chondrocytes express FGFR3 and prehypertrophic/hypertrophic chondrocytes express FGFR1. These pathways inhibit the proliferation of chondrocytes, thereby limiting the longitudinal growth of bones. Thus, activating mutations in FGFRs impede linear growth and cause skeletal phenotypes such as achondroplasia and hypochondroplasia. Accelerated linear growth and epiphyseal growth plate maturation in obese children, even in the setting of decreased GH production may be due to effects of increased insulin concentrations and activation of the insulin receptor in the growth plate. Leptin, increased in obese children, has direct effects on skeletal growth centers, enhancing chondrocyte proliferation and subsequent cell differentiation. Leptin also increases growth plate aromatase activity{this may explain why some obese children are taller than normal and others are shorter based on differential responses to estrogen} which along with estrogen produced through adipose tissue aromatization, accelerates skeletal maturation. Parathyroid hormone-related protein (PTHrP) supports chondrocytes and maintains the width of the growth plate. Mutations affecting PTHrP action (e.g. Gs-alpha) can result in a shortening of the proliferating zone, accelerated differentiation of hypertrophic chondrocytes, premature closure of the growth plate, and short stature. Vitamin D facilitates normal linear growth indirectly by increasing intestinal calcium and phosphate absorption, but vitamin D metabolites produced locally in the growth plate also decrease the proliferation of chondrocytes through the PTHrP pathway. Thus, the full effect of vitamin D on the growth plate physiology is incompletely understood.”

The paper some options for treatment for increasing growth plate based growth.  I recommend reading the whole paper.  I highlighted some stuff here because it does a great job explaining the mechanics of growth plate based height increase.

This is a huge find because it means that we may actually be able to pull on bones to make them longer.  Now it’s easier to deform bones by bending than it is by pulling on them but bending generates both tensile and compressive forces so you’d have to find a way to bend the bone in two parts at once to balance the compressive forces to achieve length.  Lateral compressive forces are axial tensile forces so this is why something like tapping can be beneficial to achieve length.  Don’t think that sleeping in a “rack” position can achieve this kind of pull the problem is that the pull forces are observed muscle by the muscles and ligaments which only pull the bone at the enthesis(which not surprising is longer and thicker than other parts of the bone), you’d have to find a way to generate pull directly on the bone itself.  Also, consider that sleeping in the rack position could potentially cut off circulation when you’re not awake to do anything about it.

If corsets generated bone shape increase via plastic deformation rather than traditional bone modeling with osteoclast absorption and osteoblast deposition that is a huge find because bone modeling is not likely to result in an increase in length unless osteoblast deposition occurs at the longitudinal ends of bones.

Here’s the citation:

Something like scoliosis bracing has always thought to only be beneficial during development as as a means to alter spinal development mainly through altering growth via compression and tension on the growth plate.  Something like artificial cranial deformation was thought only to work in the youth.  If something like the corset can change the spine as an adult than maybe bracing can too.

The key step is catabolism.  HGH increases bone turnover which involves both catabolism and anabolism of bone.  So we need to not only stimulate bone growth but bone degradation as well to allow the bone growth to be of a less mature cell type.