Update:  I’m still hard at work for a methodology to grow taller.  It’s just mostly a lot of self experimentation.  Most scientific studies seem to be a lot of more of the same stuff like IGF2 is key.

Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-β signaling.

The question is:  Can excessive subchondral bone formation make you taller?

Judging from this picture here yes it should.

“Transforming growth factor-β (TGF-β) has been demonstrated as a potential therapeutic target in osteoarthritis. However, beneficial effects of TGF-β supplement and inhibition have both been reported, suggesting characterization of the spatiotemporal distribution of TGF-β during the whole time course of osteoarthritis is important. To investigate the activity of TGF-β in osteoarthritis progression, we collected knee joints from Dunkin-Hartley (DH) guinea pigs at 3, 6, 9, and 12-month old (n = 8), which develop spontaneous osteoarthritis in a manner extraordinarily similar to humans. Via histology and micro-computed tomography (CT) analysis, we found that the joints exhibited gradual cartilage degeneration, subchondral plate sclerosis[a thickening of the subchondral bone where it begins to develop cysts, hardens, and thickens], and elevated bone remodeling during aging. The degenerating cartilage showed a progressive switch of the expression of phosphorylated Smad2/3 to Smad1/5/8, suggesting dual roles of TGF-β/Smad signaling during chondrocyte terminal differentiation in osteoarthritis progression. In subchondral bone, we found that the locations and age-related changes of osterix(+) osteoprogenitors were in parallel with active TGF-β, which implied the excessive osteogenesis may link to the activity of TGF-β. Our study, therefore, suggests an association of cartilage degeneration and excessive bone remodeling with altered TGF-β signaling in osteoarthritis progression of DH guinea pigs.”

“knee osteoarthritis is a disease of the entire joint, including synovitis, meniscal degeneration and malposition, periarticular bone overgrowth{periarticular bone is bone that surrounds the joint overgrowth of this bone should be good for height growth}, and articular cartilage destruction”

” In response to the altered mechanical environment, the bone–cartilage functional unit adjusts the architecture via cells’ adaptations. However, a discrepancy of repair capacity between the chondrocytes and other skeletal cells is thought to further accelerate the progression of osteoarthritis. Furthermore, it is widely appreciated that the subchondral plate and trabecular bone show different responses, where thickening of the plate can be identified along with osteopenic trabeculae at the advanced stage of osteoarthritis”

“ALK5/Smad2/3 route restrains terminal differentiation of chondrocytes, whereas the ALK1/Smad1/5/8 route induces the differentiation. The increase in ALK1/ALK5 ratio in chondrocytes may contribute to the cartilage degeneration.On the other hand, TGF‐β acts as a coupling factor to induce the migration of mesenchymal stem cells (MSCs) to bone resorption sites, implying its potential function in rebalancing bone resorption and formation.  Inhibition of TGF‐β signaling in subchondral bone resulted in higher bone quality and less cartilage degeneration in an induced‐osteoarthritis model”

If you look at figure 3 you can see increased subchondral bone height although it should be noted that these pigs were still growing.

“The tidemark advancement is a result of the pathological endochondral ossification at the calcified zone of cartilage”

“Smad2/3 signaling is essential to repress the hypertrophy of chondrocyte, whereas Smad1/5/8 route, namely bone morphogenetic protein (BMP) pathway, is required for chondrocyte terminal differentiation. Inhibition of the Smad1/5/8 signaling pathway led to reduced or delayed chondrocyte hypertrophy. Increase in ALK1/ALK5 ratio was associated with age and osteoarthritis and dominant ALK1/Smad1/5/8 pathway was found in advanced stage of induced osteoarthritis”

Here’s an interesting Jeffrey Baron paper who’s done a lot of growth research.  Essentially, smaller bones undergo senescence earlier so the chondrocytes undergo less proliferation cycles.

Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions.

“Bones at different anatomical locations vary dramatically in size. For example, human femurs are 20-fold longer than the phalanges in the fingers and toes. The mechanisms responsible for these size differences are poorly understood. Bone elongation occurs at the growth plates and advances rapidly in early life but then progressively slows due to a developmental program termed “growth plate senescence.”{estrogen may be responsible for this senescence} This developmental program includes declines in cell proliferation and hypertrophy, depletion of cells in all growth plate zones, and extensive underlying changes in the expression of growth-regulating genes. Here, we show evidence that these functional, structural, and molecular senescent changes occur earlier in the growth plates of smaller bones (metacarpals, phalanges) than in the growth plates of larger bones (femurs, tibias) and that this differential aging contributes to the disparities in bone length. We also show evidence that the molecular mechanisms that underlie the differential aging between different bones involve modulation of critical paracrine regulatory pathways, including insulin-like growth factor (Igf), bone morphogenetic protein (Bmp), and Wingless and Int-1 (Wnt) signaling. Taken together, the findings reveal that the striking disparities in the lengths of different bones, which characterize normal mammalian skeletal proportions, is achieved in part by modulating the progression of growth plate senescence.”

<-So if the change in body proportions is a result of senescence shouldn’t the body proportions be different in someone with different senescence such as someone with no estrogen receptors.  We know that body proportions are different in dwarfism.

“. The rate of long bone elongation (length/time) is primarily determined by the rate of chondrocyte proliferation (cells/time) per column multiplied by the cell height (length/cell) achieved after chondrocyte hypertrophy”

“During mammalian embryonic development, all long bones form from mesenchymal condensations of similar size. However, different long bones diverge in growth rate, ultimately leading to dramatic differences in bone length. ”

“the rates of bone elongation at the proximal tibia and the distal femur, measured by calcein labeling, were greater than those of the metacarpal bones and proximal phalanges. Some previous studies have attributed these differences in growth rate between bones to differences in the size attained by the hypertrophic chondrocytes of the growth plate. However, the rate of bone elongation is also dependent on chondrocyte proliferation and is approximated by the height of the terminal hypertrophic chondrocyte in the column multiplied by the chondrocyte proliferation rate per cell column ”

” a chondrocyte near the top of the growth plate in the larger bones would go through more rounds of cell division before slowing and ceasing proliferation compared with the smaller bones.”<-So how do we get chondrocytes to undergo more rounds of cell division?  There are number of factors.    A number of senescence related genes are mentioned in the study itself.  IGF2 is a key one.

“Growth plate senescence is characterized not only by a decline in proliferation rates but also by a gradual structural involution of the growth plate, including declines in the overall height of each growth plate zone and the number of chondrocytes in each zone.”

Note:  I’m still hard at work at finding a methodology of growing taller and am investigating non-LSJL method.

Finite-element analysis of the mouse proximal ulna in response to elbow loading.

“Bone is a mechano-sensitive tissue that alters its structure and properties in response to mechanical loading. We have previously shown that application of lateral dynamic loads to a synovial joint, such as the knee and elbow, suppresses degradation of cartilage{We also should investigate inducing endochondral ossification of the cartilage, perhaps Lateral Joint Loading could be involved in that} and prevents bone loss in arthritis and postmenopausal mouse models, respectively. While loading effects on pathophysiology have been reported, mechanical effects on the loaded joint are not fully understood. Because the direction of joint loading is non-axial, not commonly observed in daily activities{This is what’s so interesting about lateral joint loading, any height increase method has to be something that people do not do in ordinary activities as otherwise people would already have discovered that it makes you taller}, strain distributions in the laterally loaded joint are of great interest. Using elbow loading, we herein characterized mechanical responses in the loaded ulna focusing on the distribution of compressive strain. In response to 1-N peak-to-peak loads, which elevate bone mineral density and bone volume in the proximal ulna in vivo, we conducted finite-element analysis and evaluated strain magnitude in three loading conditions. The results revealed that strain of ~ 1000 μstrain (equivalent to 0.1% compression) or above was observed in the limited region near the loading site, indicating that the minimum effective strain for bone formation is smaller with elbow loading than axial loading{This is likely due to increases in fluid flow and/or hydrostatic pressure resulting in most of the adaptive response}. Calcein staining indicated that elbow loading increased bone formation in the regions predicted to undergo higher strain.”

“dynamic strain in bone matrix and strain-induced fluid flow in the lacuno-canalicular network are two of the major contributors to mechanotransduction in bone”

“Unlike axial loading, such as in ulna and tibia loading, joint loading employs lateral loads that sandwich a synovial joint, such as the knee, ankle, and elbow”<-I have not heard joint loading described this way before.  This description emphasizes the lateral compression force.

” we determined the strain distribution to the ulna in response to elbow loading using a mouse model and finite-element (FE) analysis. Daily loading with 1-N peak-topeak force at 1 Hz for 5 min was applied to ovariectomized (OVX){OVX mice simulates osteoperiosis} mice as well as sham-OVX mice (control mice){we are more interested in this group}, and bone mineral density (BMD) was measured at the site of loading after 4 weeks of loading. ”

” We employed three loading configurations: load and a single point of support, load and a three-point support, and load across soft tissues that may mimic surrounding skin and muscle”

” The lateral loads to the elbow were given 5 min per day for 5 weeks using 1-N force (peak-to-peak) at 5 Hz to the right arm, and left arm data were used as a contralateral control. ”

You can see the bone formation in the control group.  Definitely doesn’t indicate that it increases height but it indicates that it does something which is a start.  There seems to be an increase in bone width as well which is harder than just increasing the trabecular bone from within which is also very good although these mice are 12 week old female mice.  But the increase in bone width indicates the possibility of abnormal effects going on which would be needed to induce height growth.

” We employed three loading and boundary conditions in response to elbow loading with 1-N loads: lateral loads applied at two opposing locations; lateral loads applied at a single site on one side and three supporting sites on the other side; and lateral loads on a pair of soft disks that sandwiched the elbow.”<-it’ll be interesting to see which is best.  I think the soft disks would really diminish the load.

“Compression of a pair of soft-tissue disks induced multiple strain spots that were widely distributed from the proximal tip to the whole elbow joint ”

“Elbow loading generates artificial lateral forces that are rarely encountered during routine physical activity. Unlike axial or bending loads with ulna loading or tibia loading, the mechanical response of synovial joints, such as the elbow, to lateral loads has not been fully characterized”You can’t really see any abnormal bone formation here like you could in the earlier image and they look to be similar sites.  “Calcein-stained cross sections of the proximal ulna distal to the trochlear notch” whereas the earlier one is “c μCT images of the cross sections of the proximal ulna, ~ 1 mm distal to the edge of the trochlear notch”

” Compared to strain at the single loading site, three supporting sites significantly reduced
the maximum compressive strain by ~tenfold (from ~ 2% in the dark blue label to ~ 0.1% in the cyan level). “<-So maybe one loading site is best.  Multiple loading sites would counter the deformation and act as a sort of stabilizing force [cancel each other out].  “strains exceeding 0.1% (1000 μstrain) are confined to the vicinity of the loading site and supporting points”<-So maybe in someone that is growing we would we want to load directly near the growth plate or in an adult maybe near the articular cartilage.

Not very much height stuff but good to see it still being worked on.

{Tyler-This was a post by Michael John.  I am still very much working towards finding a way to grow taller.  Now I am focus on in inducing endochondral ossification of the articular cartilage.  I am growing through old studies.  It’s just a lot of studies are more of the same}

Note: The efficacy of this compound has been very controversial

I have been spending a ridiculous amount of time recently doing a LOT of research on the chemical compound known as Menaquinone-7, aka MK7, aka Vitamin K2. There has been a lot of research that I have found which confirms this idea that MK7 Supplements will lower the risk of hip femoral neck fractures in post menopausal women.

A recent PubMed Study “Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women.” finally has admitted to the idea that it may not just be the Bone Mineral Density that can be dramatically reduced in its decreasing rate, but maybe the overall height of a person, at least slightly.

Let me quote the following…”MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae.”

Something that has been worrying me for so long, from looking at so many claims of professional MDs is that since the most well known type of food source which has high concentrations of Vitamin K2 is Natto, was this “Why is it that if the Japanese are eating so much Natto (Since Natto is such a critical part of the Japanese diet, unlike any other country in the world) and soy based products relative to other ethnic groups, do Japanese women (or even Eastern Asian women in general) seem to have the highest rates of osteoporosis?”

Wouldn’t eating Natto have the opposite effect?

Is it just a racial thing, where different races actually have different levels  of BMD on average?

The Science behind Menaquinone-7

It seems that with MK7 at least, it can stimulate the level of osteocalcin and GLA in the body. the osteocalcin and GLA have a certain area of their molecular structure which allows them to chelate the Calcium atoms out of the soft tissue areas of the body, like the blood vessels. Remember that one of the things that happen as we get older is that there is a sort of plaque buildup in our blood vessels. 20% of the buildup in our vessels is calcium in nature. Somehow the K2 can cause the calcium buildup in the soft tissue area/blood vessels to reverse in ossification.

What I am sure about

When the dentist Weston Price did his analysis on all those kids who didn’t seem to develop cavities back in the 30s or 50s (not sure what decade it was), he claimed that the compound was something he called Activator X. Recently people are saying that the activator X compound is just Vitamin K2, specifically the MK-7 version.

The K2 he managed to give to kids to reverse their cavities was some type of grass feed butter, combined with Cod Liver Oil. Remember what Dave Asprey has been asking the people who take his Bulletproof coffee to do? Put some grass-fed butter in it. It turns out that the Grass Feed Butter Oil has a higher than average concentration of K2 in it. Not only that, the entire idea of the possibility of reversing cavities was because I used to lurk in the Bulletproof Executive Forum , and heard other people who claim to have it happen to them. Dr. Pamela Smith has claimed in one Youtube video though that you would need a recommended 100 mcg of Menaquinone-7 to get a reasonable effect.

However, when Price did the X-rays to show that the teeth seemed to fill out, he didn’t consider the factor of Strontium, as well as the fact that to get the caries to reverse, you still need to at least put some filling on the cap of the teeth first. The hole in the center is supposed to be filled up over time from K2 supplementation.

Understanding Growth Plate Fusion(and growth plate senescence) will help us understand if these processes can be reversed.  And just as a note I am still working on devices and methodology to grow taller.

A Computed Microtomography Method for Understanding Epiphyseal Growth Plate Fusion.

“The epiphyseal growth plate is a developmental region responsible for linear bone growth, in which chondrocytes undertake a tightly regulated series of biological processes. Concomitant with the cessation of growth and sexual maturation, the human growth plate undergoes progressive narrowing, and ultimately disappears. Despite the crucial role of this growth plate fusion “bridging” event, the precise mechanisms by which it is governed are complex and yet to be established. Progress is hindered by the current methods for growth plate visualization; these are invasive and largely rely on histological procedures. Here, we describe our non-invasive method utilizing synchrotron X-ray computed microtomography for the examination of growth plate bridging, which ultimately leads to its closure coincident with termination of further longitudinal bone growth. We then apply this method to a dataset obtained from a benchtop micro computed tomography scanner to highlight its potential for wide usage. Furthermore, we conduct finite element modeling at the micron-scale to reveal the effects of growth plate bridging on local tissue mechanics. Employment of these 3D analyses of growth plate bone bridging is likely to advance our understanding of the physiological mechanisms that control growth plate fusion.”

“It is the terminally differentiated hypertrophic chondrocyte, which mineralizes its surrounding extracellular matrix. This process, thought to involve membrane-limited matrix vesicles, is biphasic and tightly regulated by a number of enzymes and factors including alkaline phosphatase (Alpl), PHOSPHO1, the ankylosis protein (Ank), ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (Enpp1) ”

“as growth slows, the human growth plate undergoes progressive narrowing as bony bridges form and span its width. This ultimately leads to complete growth plate closure and the cessation of human growth. These bone bridges are also known to form upon growth plate injury, thought to be through an intramembranous ossification mechanism”

“in two genetic mutations resulting in estrogen deficiency (in the estrogen-receptor gene, and in the CYP19 gene), the growth plate fails to fuse and growth persists, albeit rather slowly, into adulthood”

“Evidence from studies in both humans and rats revealed the cessation of growth long before any histological evidence of growth plate fusion, suggesting that epiphyseal fusion is a marker of growth cessation and not its cause “<-Thus it may be possible to renew growth plate growth by reversing cessation and not fusion.

“young (8 weeks old) CBA wild-type mice, growth plate bridging is associated with locations that contain high local von Mises stresses. Moreover, we reveal that with aging an increased number and density of growth plate bridges is observed”

” in wild-type mice, increased growth plate bridging translates into increased stresses in the bone directly beneath the growth plate.”<-So maybe these stresses contribute to growth plate closure.

“At 8 weeks, few bridges are detected and overall the growth plate is squeezed in a “sandwich” configuration. This suggests that compressive hydrostatic stresses are engendered across major volumes and that higher shear stresses are generated only at the peripheral edges of the growth plate. Yet, the results of numerous mechanobiological models support that growth and ossification is accelerated by tensile strain (or shear stresses) and that cartilage tends to be maintained by hydrostatic compressive stress“<-so for a longer growth period we need to encourage hydrostatic compressive stress.

A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate.

“Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification. However, it remains unknown how this supply is maintained throughout childhood growth. Chondroprogenitors in the resting zone are thought to be gradually consumed as they supply cells for longitudinal growth, but this model has never been proved. Here, using clonal genetic tracing with multicolour reporters and functional perturbations, we demonstrate that longitudinal growth during the fetal and neonatal periods involves depletion of chondroprogenitors, whereas later in life, coinciding with the formation of the secondary ossification centre, chondroprogenitors acquire the capacity for self-renewal, resulting in the formation of large, stable monoclonal columns of chondrocytes{if these chondroprogenitors never become senescent then we can grow forever}. Simultaneously, chondroprogenitors begin to express stem cell markers and undergo symmetric cell division. Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signalling pathways. Our findings indicate that a stem cell niche develops postnatally in the epiphyseal growth plate, which provides a continuous supply of chondrocytes over a prolonged period.”

“CD73 (encoded by Nt5e) was among the most upregulated stem cell surface markers (4.9 ± 1.2-fold; P28 versus P2; P = 0.018) and immunohistochemical analysis confirmed de novo expression of CD73 at P28 (markers for cell proliferation (Ki67) and differentiation (MEF2C) were controls for developmental changes”

“Cells in the growth plate might also orient as a result of migration or stacking due to tissue polarization, which is reflected by the orientation of primary cilia. Cilia on flat chondrocytes, but not on chondroprogenitors, were polarized (with 61.3 ± 4.8% and 32.8 ± 2.2% of cilia, respectively, oriented longitudinally, P = 0.005, n = 3;”

3j is supposed to summarize it