What can other species teach us about height growth?

Other species have different genetic composition than us but we can mimic the effects that different genetics have on phenotype(our goal is a tall phenotype after all).  By analyzing species, that are taller than normal we can figure out why they are tall and see if we can mimic the conditions that made them tall?  For example, if they are taller due to high or low serum concentrations of certain compounds we can alter our own composition of those compounds.

We can also analyze the growth of species who are shorter than normal to see if we can reverse any processes that stunt growth.

The Ontogenetic Osteohistology of Tenontosaurus tilletti.

"Tenontosaurus tilletti is an ornithopod dinosaur. Here I describe the long bone histology of T. tilletti and discuss histological variation at the individual, ontogenetic and geographic levels. The ontogenetic pattern of bone histology in T. tilletti is similar to that of other dinosaurs, reflecting extremely rapid growth early in life, and sustained rapid growth through sub-adult ontogeny. But unlike other iguanodontians, this dinosaur shows an extended multi-year period of slow growth as skeletal maturity approached[so what we can learn from this dinosaur is how to extend the period of growth as skeletal maturity approaches]. Evidence of termination of growth(e.g., an external fundamental system) is observed in only the largest individuals[Interesting that termination of growth is only present in larger individuals perhaps the process of growth termination is height growth stimulating], although other histological signals in only slightly smaller specimens suggest a substantial slowing of growth later in life. Histological differences in the amount of remodeling and the number of lines of arrested growth varied among elements within individuals, but bone histology was conservative across sampled individuals of the species, despite known paleoenvironmental differences between the Antlers and Cloverly formations. The bone histology of T. tilletti indicates a much slower growth trajectory than observed for other iguanodontians (e.g., hadrosaurids), suggesting that those taxa reached much larger sizes than Tenontosaurus in a shorter time[so we can also use this dinosaur to learn how to increase growth rate]."

<-So these dinosaurs are shorter than normal and it's likely a result of growth rate slowing at senescence.  The largest dinosaurs were the ones who terminated growth the fastest.  This could possibly indicate that instead of trying to extend growth, we should be trying to make growth faster and then trying to form new growth plates with a method like LSJL.

Regardin Juvenile Tenontosaurus: "In all long bones of this size class, the cortex is thicker than the diameter of the medullary cavity and is comprised of woven primary bone tissues with large, longitudinally oriented simple vascular canals that do not open to the surface of the bone. The vascular canals are circular or subelliptical in cross-section and smaller in diameter compared to those of the perinate. These canals are almost always arranged circumferentially in the cortex, and often show strong radial patterns as well, especially in the humerus and ulna. Osteocytes are dense throughout the cortex. These are organized around the vascular canals, but in the interstices between them, the osteocytes are randomly arranged and randomly oriented. In all specimens examined, the medullary cavity was filled by calcite crystals, and in most cases a thin band of avascular lamellar bone lines the edge of the marrow cavity, delimiting the endosteal boundary of the cortex. This band of lamellae suggests a pause in the expansion of the medullary cavity at this stage of growth. No LAGs or secondary osteons occur in any of the bones of this size class."<-Note that these dinosaurs had a rapid growth in early life.  Some of these bone properties may have been responsible for that rapid growth.

Regarding SubAdult Tenontosaurus: "Subadults always retain a thick cortex relative to the size of the medullary cavity, but at this growth stage, cortical bone tissues are removed as the medullary cavity expands.

For all elements, the entire cortex is composed of well-vascularized woven bone. Except in the fibula, almost all of the visible cortical bone tissues are primary tissues vascularized by simple canals or (more commonly) primary osteons, but secondary osteons are visible endosteally in all subadult elements sampled. The amount and extent of secondary remodeling varies with the size (age) of the individual and by element. Younger individuals have secondary osteons only in the internalmost cortex, but these spread throughout the inner cortex and eventually into the mid-cortex in older animals. The tibia and femur show much less secondary remodeling compared to the humerus, ulna, and fibula.

All subadult elements show many longitudinally oriented canals throughout the cortex, and these are smaller in diameter compared to those of juveniles or perinates. More of these canals anastomose than in juveniles or perinates, and these anastomoses are longer (connect more longitudinal canals) in larger individuals[an anastomose is something that joins blood vessals, note that larger individuals had longer anastomoses which indicates that individuals who wish to grow taller should try to connect more longitudinal canals unless of course the longer anastomoses are the byproduct rather than the cause of height growth]. The anastomoses tend to be more circumferential in orientation in the tibia and femur, and more radial in the humerus and especially the ulna, but short connections occur in every direction in all elements. In larger subadults, true plexiform/laminar organization can be observed in the tibia, femur, and humerus. Interstitial osteocytes are dense throughout the subadult cortex and show no preferred arrangement relative to each other, nor a preferred orientation relative to the long axis of the bone.

All elements of subadult Tenontosaurus exhibited one or more LAGs[Lines of Arrested Growth or areas of broken bone deposition]. These often formed as “double LAGs”, i.e., two very closely-spaced LAGs that likely did not represent an entire year of growth between them. In many tibial sections, especially those from older individuals, the bone texture changed within each zone. In some elements, immediately following a LAG, a very thin band of parallel-fibered or weakly-woven bone tissue is present. This very quickly changes to woven bone, in which the collagen fibers were coarse and disorganized. The bone would become progressively less woven through the zone and leading up to the subsequent LAG. This suggests, for at least some elements, that the bone depositional rate decreased through the year, although lamellar-zonal bone (which is deposited much more slowly) was never observed in a subadult, and zonal width did not decrease dramatically in this size class."<-The sub adult region is likely when growth slowed down.

Regarding Adult Tenontosaurus: "[There were] signs of dramatically slowed growth in adult Tenontosaurus.  Extensive remodeling (i.e., several generations of secondary osteons) of the inner, mid- and even outer cortex was observed in all elements. Additionally, the zonal cycles of decreasing growth rates truncating in a LAG observed in the larger subadults is more pronounced in adults. Moving periosteally through the cortex, the woven-to-less-woven bone transition becomes a weakly-woven-to-parallel-fibered pattern, and ultimately lamellar bone tissue is deposited in the outermost cortex. These transitions are accompanied by trends in decreasing vascularity (in terms of number of canals, not their size), decreasing vascular complexity (number and kinds of anastomoses), decreasing numbers of osteocytes, and decreasing zonal width. Together, these signals indicate several years of sustained slow growth rates in adult Tenontosaurus before an ultimate truncation of growth."

"Throughout early ontogeny and into subadulthood, Tenontosaurus tilletti is characterized by bone tissues associated with fast growth. The cortex of all of the major long bones exhibits woven bone tissue, high levels of vascularization, complex patterns of vascular connectivity and organization, and high osteocyte density[so to grow taller we want to increase levels of woven bone tissue, more vascular connectivity and higher osteocyte density]. These histological characteristics suggest that T. tilletti maintained a rapid growth rate at least to the point of reproductive maturity. However, at some point in the subadult stage, Tenontosaurus transitioned to a slower growth regime. These slower growth rates are initially reflected in the woven texture of the cortex of subadults, but in adults, further decreases in osteocyte and vascular density, smaller zonal widths, and ultimately the presence of an EFS[External Fundamental System or the evidence of growth termination] suggest prolonged (several years) of slow growth rates before the termination of growth. These trends in bone histology strongly suggest asymptotic (“determinate”) skeletal growth for Tenontosaurus, consistent with what is observed in other dinosaurs"

"Beginning in subadulthood, Tenontosaurus changed its growth regime and began depositing parallel-fibered bone tissue in much narrower zones."

So what we can learn from these dinosaurs is that to grow taller we likely want to increase osteocyte density(osteocytes detect signals from interstital fluid flow which may be how it relates to height growth).  Osteocyte density is likely though a symptom rather than a cause of upcoming height increase.  More dense osteocytes indicate that the bone is underdeveloped relative to the number of osteocytes.

Woven bone formation is likely also a symptom rather than a cause of height growth.  Woven bone is a sign of new bone formation such as the case with gap repair.

That leaves vascularization which plays a role in distraction osteogenesis.  The fact that immature bone is so vascularly organized indicates that vascularization is not a symptom of bone that is ready to grow longer but rather a cause as you'd expect immature bone to be disorganized.  Adult dinosaur bone was characterized with less cartilage canals and less vascular complexity.

This indicates that proteins involved in vascularization like VEGF, MMP-9, and osteoclasts are important for height growth.  Mechanical stimulation for instance may increase levels of VEGF.  Of course VEGF is linked to Estrogen and Estrogen reduces height when levels are too high.  Thus it may not be a simple case of more of these compounds equals more height growth.  You may need a complex interplay of compounds to maximize vascularization to encourage height growth.

Given previous evidence of vascularization being linked to height growth, like hydrostatic pressure which can induce chondrogenesis being influenced by vascularization, this further exemplifies that vascular factors are huge influence upon height and anything that influences bone vascularization like VEGF, Estrogen, MMPs, etc. should be heavily analyzed for influence on height growth.


Temporal analysis of rat growth plates: cessation of growth with age despite presence of a physis.

"Despite the continued presence of growth plates in aged rats, longitudinal growth no longer occurs. We studied the growth plates of femurs and tibiae in Wistar rats aged 62-80 weeks and compared these with the corresponding growth plates from rats aged 2-16 weeks. During skeletal growth, the heights of the plates, especially that of the hypertrophic zone, reflected the rate of bone growth. During the period of decelerating growth, it was the loss of large hydrated chondrocytes that contributed most to the overall decrease in the heights of the growth plates. In the old rats we identified four categories of growth plate morphology that were not present in the growth plates of younger rats: (a). formation of a bone band parallel to the metaphyseal edge of the growth plate, which effectively sealed that edge; (b). extensive areas of acellularity, which were resistant to resorption and/or remodeling; (c). extensive remodeling and bone formation within cellular regions of the growth plate; and (d). direct bone formation by former growth plate chondrocytes. These processes, together with a loss of synchrony across the plate, would prevent further longitudinal expansion of the growth plate despite continued sporadic proliferation of chondrocytes."

"In rats, the rate of growth increases between 1 and 5 weeks, then declines until skeletal maturity, which is achieved by 11.5–13 weeks. Bones still continue to grow, albeit at a reduced rate, until ∼26 weeks of age, after which growth virtually ceases in rats"

"At 2 weeks, approximately half of the cartilaginous epiphysis (chondroepiphysis) had been replaced by the secondary ossification center. At this age, the height of the growth plate could not be taken as the distance between the primary spongiosa and the secondary ossification center (bony epiphysis), because approximately one third of that distance still represented the epiphyseal cartilage of the chondroepiphysis rather than growth plate cartilage."

"At 2 and 4 weeks, resorption took place at the epiphyseal and metaphyseal borders of the growth plates, whereas from 12 weeks onwards resorption was confined to the metaphyseal border. In old rats, TRAP activity was either completely absent or was present in the matrix at the reversal line which, in this case, marked the border between horizontal bone deposition and growth plate cartilage"

"features [of 82 week old rat growth plate versus 8 week old rat growth plate] are (1) horizontal deposition of bone matrix, (2) acellular areas, (3) within growth-plate remodeling, and (4) intralacunar bone formation."

"In the aged rats, spongiosa was absent in some regions, presumably as a consequence of resorption. In such areas, bone matrix was directly apposed to the cartilage, parallel to the growth plate, effectively sealing the growth plate with bone at the metaphyseal border."

"In the growth plates of young rats, the cartilage core, which forms the center of the spicules of primary and secondary spongiosa, is usually thin and is only detectable only at higher magnification. By contrast, some spicules of aged rats contained a wide core of cartilage that was evident even at low magnifications and often persisted well below the average height of the growth plate. Closer examination of these cartilage cores revealed that no cells were present. Such acellular regions could extend from the former reserve zone to the vascular front and beyond into the spongiosa, suggesting that the cartilage matrix was more resistant to resorption than adjacent cellular matrix. Acellular areas were also identified in the growth plates of 12-and 16-week-old animals, although less frequently. Adjacent to acellular regions, regions of high cellularity were frequently present"

"the osteogenic differentiation of chondrocytes in the old rats was not a gradual further differentiation of chondrocytes but was rather a transdifferentiation in which acquisition of the osteogenic phenotype coincided with loss of the chondrogenic phenotype."

All these changes seem consistent with genetic dysregulation rather than programmed senescence.


Aberrations of cell cycle and cell death in normal development of the chick embryo growth plate.

"The epiphyses of femurs from 7.5-15 day chicken embryos were studied by electron microscopy. Several forms of aberrant cell cycles were present: (1) in the perichondrium, polyploid metaphases, segmentating large (giant) cells, and mitotic catastrophe (midway between mitosis and apoptosis) were observed; (2) in the resting zone, premature chromosome condensation was found; (3) in the proliferative zone, approximately 5% of divisions were aberrant, representing most often mitosis restitution from metaphase and more seldom from the anaphase; (4) in all layers, 'dark chondrocytes' representing a premortal form of hypersecretory cells undergoing often a-mitotic nuclear segmentation were present. Many of the aberrations of cell cycle were combined with cell death. These deviations omitting or adapting the cell cycle check-points represent evidently the normal epigenetic mechanisms of development and repair. At the same time, by origin and appearances they seem very close to the loss of the growth control displayed by malignant tumours."

"All these aberrations were associated with tetraploidy and mostly with curtailments of the mitotic cycle. "

Changes in the expression of Fas, osteonectin and osteocalcin with age in the rabbit growth plate.

"The Fas receptor is a mediator of the apoptotic signal in some systems. We studied its expression in situ in growth plates of rabbits aged from five to 20 weeks. In addition, we investigated the immunolocalisation in the growth plates of the bone proteins, osteonectin and osteocalcin, and the changes in their expression with age. The Fas-positive chondrocytes were found mostly in the hypertrophic zone, as were the osteonectin-positive and osteocalcin-positive cells. The percentage of Fas-positive cells increased with age whereas little change was found in the number of osteonectin-positive and osteocalcin-positive chondrocytes. Many of the Fas-positive chondrocytes were also TUNEL-positive. This strongly suggests that apoptosis in the growth plate is mediated through the Fas system. Double immunostaining for osteocalcin and Fas showed that not all hypertrophic chondrocytes were of the same cell type. Some chondrocytes stained for osteocalcin only, others for Fas only, while some were positive for both"

Network based transcription factor analysis of regenerating axolotl limbs.

"We used the human orthologs of proteins previously identified by our research team as bait to identify the transcription factor (TF) pathways and networks that regulate blastema{a group of stem cells} formation in amputated axolotl{a water salamander} limbs. The five most connected factors, c-Myc, SP1, HNF4A{down in LSJL}, ESR1 and p53 regulate ~50% of the proteins in our data. Among these, c-Myc and SP1 regulate 36.2% of the proteins. c-Myc was the most highly connected TF (71 targets). Network analysis showed that TGF-β1 and fibronectin (FN) lead to the activation of these TFs. We found that other TFs known to be involved in epigenetic reprogramming, such as Klf4, Oct4, and Lin28{lin28b is up in LSJL} are also connected to c-Myc and SP1.

We found that the TFs, c-Myc and SP1 and their target genes could potentially play a central role in limb regeneration."

"Urodele amphibians (axolotls, salamanders and newts) regenerate amputated limbs perfectly throughout larval and adult life"

"Blastema cells originate by a reverse developmental process in which the tissue matrix near the amputation plane is degraded by proteases, releasing both mature cells that are reprogrammed to a mesenchymal stem cell-like state, and muscle stem cells (satellite cells). Within a few days after amputation, these cells accumulate under the apical epidermal cap (AEC), where they proliferate and are patterned into the missing limb parts."

" we found that TGF-β1 (transforming growth factor - beta 1) could potentially lead to the activation of SP1 and then to the expression of FN (fibronectin), which is produced by the blastema cells and the AEC. In turn, FN activates c-Myc via integrins and the Wnt pathway. Within these pathways we identified several TFs such as SMAD3 (mothers against decapentaplegic homolog 3), which may be involved in limb regeneration. In addition, Klf4 (kruppel-like factor 4), Oct4 (octamer-binding protein 4), and Lin28, TFs common to embryonic stem cells, induced pluripotent cells (iPSCs) and blastema cells, were also found to be connected to c-Myc and SP1."

Msx1 and Notch1 are also factors involved in limb regeneration.

"c-Myc activation from FN involves the cell adhesion proteins talin, FAK1 (focal adhesion kinase1), c-Src, Paxillin, ILK (integrin-linked protein kinase) and components of the canonical Wnt signaling pathway (GSK3-β-glycogen synthase kinase-3 beta, β-catenin, and Tcf/Lef (T-cell-specific transcription factor/lymphoid enhancer-binding factor 1)"

"molecular interactions of Wnt2b with Tbx5 that are responsible for limb identity and outgrowth"

Detailed comparison of LSJL genes and limb regeneration genes To Be Done.


Xenopus laevis as a novel model to study long bone critical-size defect repair by growth factor-mediated regeneration.

"We used the tarsus of an adult Xenopus laevis frog as an in vivo load-bearing model to study the regeneration of critical-size defects (CSD)[defects too large to be repaired naturally] in long bones. We found the CSD for this bone to be about 35% of the tarsus length. To promote regeneration, we implanted biocompatible 1,6 hexanediol diacrylate scaffolds soaked with bone morphogenetic proteins-4 and vascular endothelial growth factors. In contrast to studies that use scaffolds as templates for bone formation, we used scaffolds as a growth factor delivery vehicle to promote cartilage-to-bone regeneration. Defects in control frogs were filled with scaffolds lacking growth factors. The limbs were harvested at a series of time points ranging from 3 weeks to 6 months after implantation and evaluated using micro-computed tomography and histology. In frogs treated with growth factor-loaded scaffolds, we observed a cartilage-to-bone regeneration in the skeletal defect. Five out of eight defects were completely filled with cartilage by 6 weeks. Blood vessels had invaded the cartilage, and bone was beginning to form in ossifying centers. By 3 months, these processes were well advanced, and extensive ossification was observed in 6-month samples. In contrast, the defects in control frogs showed only formation of fibrous scar tissue."

"Instead of attempting to promote regeneration by direct bone deposition on a scaffold, we induced the intercalary regeneration of the missing bone by implanting a biocompatible scaffold loaded with growth factors specifically selected to induce cartilage to form in the defect, bridge the bone gap, and then convert this cartilage template to bone. We selected BMP-4 and VEGF as the growth factors to be used because BMP-4 is essential for the development of cartilage templates and is induced early in fracture repair, and VEGF induces blood vessel formation and is critical for the conversion of hypertophic cartilage to bone"

"The presence of the scaffold alone did not promote cartilage or bone formation in the tarsus gap."


Adipose-derived stem cells from the brown bear (Ursus arctos) spontaneously undergo chondrogenic and osteogenic differentiation in vitro.

"n the den, hibernating brown bears do not develop tissue atrophy or organ damage, despite almost no physical activity. Mesenchymal stem cells could play an important role in tissue repair and regeneration in brown bears. Our objective was to determine if adipose tissue-derived stem cells (ASCs) can be recovered from wild Scandinavian brown bears and characterize their differentiation potential. Following immobilization of wild brown bears 7-10 days after leaving the den in mid-April, adipose tissue biopsies were obtained. ASCs were recovered from 6 bears, and shown to be able to undergo adipogenesis and osteogenesis in monolayer cultures and chondrogenesis in pellet cultures. Remarkably, when grown in standard cell culture medium in monolayer cultures, ASCs from yearlings spontaneously formed bone-like nodules surrounded by cartilaginous deposits, suggesting differentiation into osteogenic and chondrogenic lineages. This ability appears to be lost gradually with age. This is the first study to demonstrate stem cell recovery and growth from brown bears, and it is the first report of ASCs spontaneously forming extracellular matrix characteristic of bone and cartilage in the absence of specific inducers."

"Remarkably, however, the cells from yearlings showed remarkable spontaneous cartilage and bone formation capacity. Interestingly, the spontaneous bone and cartilage formation appears to occur in a concurrent manner in and around the nodules, respectively, with mineralization characteristic of bone within the nodules and cartilage formation in the periphery."

"close cell-to-cell contact [is needed] for chondrogenesis to occur"