The physics of growing taller via your growth plates

Height growth occurs primarily by chondrocyte hypertrophy.  Chondrocytes expand in size in both height and width making you taller.  Now the thing is that the growth plates are in between two parts of the bone:  the epiphysis and the diaphysis.  In growth plates under IGF-1, growth plate height became taller.  However, it doesn't really make sense that a hypertrophying chondrocyte could push apart two whole bones(the epiphysis and diaphysis) to make the whole bone longer.  In the weight loading of young chicks study, loading chicks inhibited bone growth.  However, the chicks were loaded 24/7 and thus there was no time for a distraction phase.  Compressive loading has been shown to result in catch up growth as long as there was a distraction phase afterwards(like sleep).

Hypertrophying chondrocytes cannot possibly push a very sturdy epiphysis away from a diaphysis.  However, chondrocytes are a lot more elastic than bones.  Imagine two pencils stuck together by glue.  If you pull the two pencils apart, you're not likely to increase the length of the pencils but you can increase the length of the glue.  Then this glue can ossify by endochondral ossification resulting in one really long pencil.  This distraction must be critical for growth as illustrated by the chicks where chicks could not grow much taller when distraction was prohibited by non-stop loading.

Take a look at the histology of rat growth plates under LSJL.  Be sure to click on view image to see the whole thing.  You can see stem cells acquiring a chondrogenic phenotype outside of the growth plate.  Especially in the middle at the top of slide B.  Meaning that LSJL can induce chondrogenic differentiation outside of the growth plate and telomere length(+other things) willing can induce endochondral ossification there.

Now what's the difference between a growth plate and an independent stem cell differentiating into a chondrocyte.  A gap in the bone?  If you look at the LSJL slides there really is no visible gap in the bone and the LSJL rats still managed to grow taller.  The issue is primarily the bone marrow which contains mesenchymal stem cells.  You can see that in the LSJL slides that the amount of bone marrow decreased at the bottom(but not in the center).  Also, if you look at the slides in epiphyseal distraction you can see a decrease in the number of stem cells and less bone marrow.

You can grow taller as a result of an independently differentiating chondrocyte as long as distraction is allowed.  The problem is bone marrow and number of mesenchymal stem cells.  So, the growth plate gap doesn't provide a physical limit it's the bone marrow.

Here's a study that illustrates what specific characteristics of the cartilage plate that may help in producing distraction forces:

Cartilage is held together by elastic glycan strings. Physiological and pathological implications 

"Animal shapes are maintained by connective tissue extracellular matrices (ECMs). ECM shapes depend on keeping collagen fibrils in the right places, held by regular frequent proteoglycan (PG) bridges attached at specific sites. The PGs carry anionic glycosaminoglycan (AGAG) ‘strings’ that span and determine interfibrillar distances, thus holding us together. I called these repeating structures ‘shape modules’. The strings are aggregated antiparallel chains of dermochondan, keratan and chondroitan sulphates (DS, KS and CS); stabilised by hydrophobic and H-bonds. Shape modules are elastic. AGAG/AGAG interactions break under stress and reform when the stress is removed and/or they contain an elastic sugar, L-iduronate (in DS).
Cartilage ECMs are also based on shape modules. Depots therein of aggrecan, the large PG which carries many chains of CS and KS, imbibe water, thereby exerting swelling pressure[Cartilage counteracts hydrostatic pressure]. External pressure forces this water into the elastic shape modules, from whence it is returned post compression. Cartilage anisotropic responses (along and at right angles to shape module axes) to compressive and tensile stresses are now interpretable. Inability to hold collagen fibrils together results in imbibition of excess water, fissuring and erosion, characteristic of this condition."

"Iduronate in DS[DS is a GAG] underwent a sudden extension of about 10% at a critical stress of about 200 pN. This change is reversible and can be repeated as long as the molecule remains stuck across the tensioners. Iduronate is thus an elastic unit, unique in this field although we observed similar behaviour by guluronate in alginate and galacturonate in pectates"<-Elastic sugars are able to extend thus helping to explain the height growth of endochondral ossification.

Endochondral ossification: how cartilage is converted into bone in the developing skeleton.

"Hypertrophic chondrocytes die, and as they do so, the transverse septa of cartilage matrix surrounding them are broken down, leaving vertical septa largely intact, but allowing entry of the invading cells of the ossification front: blood vessels, osteoclasts (multinucleate bone-resorbing cells), and precursors of osteoblasts (bone-forming cells) and bone marrow cells. The osteoclasts assist in the removal of cartilage matrix, and the differentiating osteoblasts use the remnants of cartilage matrix as a scaffold for the deposition of bone matrix."

"Light chondrocytes have sparse endoplasmic reticulum and an inconspicuous Golgi region. Dark chondrocytes, in contrast, have well developed endoplasmic reticulum and a prominent Golgi zone; they possess numerous cytoplasmic processes, with vesicles budding from the cell surface. We have recently provided evidence that light and dark chondrocytes represent two distinct post-proliferative chondrocyte populations, with different patterns of gene expression"

"Light cells appear to disintegrate within their cell membrane, whereas dark cells undergo progressive extrusion of cytoplasm into the extracellular space; for both cell types, nuclear condensation is late and irregular"

"The actin-binding protein adseverin has recently been shown to be expressed selectively by prehypertrophic chondrocytes as well as by hypertrophic chondrocytes. Overexpression of adseverin in non-hypertrophic chondrocytes induces changes in the actin cytoskeleton, a dramatic increase in volume and expression of molecular markers of hypertrophy."

"Tg737 gene encodes the primary cilium protein polaris. Kif3a [is] a subunit of the kinesin II motor complex which is required for intraflagellar transport and the formation of cilia"

"Carminerin is a transcriptional inhibitor of nucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which generates pyrophosphate by hydrolysing extracellular adenosine triphosphate analogues"

"Loss of Gli3{up in LSJL} in Ihh-null mice restores chondrocyte proliferation, allows reactivation of PTHrP expression and delays the accelerated onset of hypertrophic differentiation seen in Ihh-null mice."

"Mutations leading to constitutive activation of the PTH/PTHrP receptor are found in patients with Jansen-type metaphyseal dysplasia, which is characterised by short limbs associated with delayed chondrocyte hypertrophy"

"mice with targeted ablation of the gene for BMP receptor 1A in chondrocytes show an expanded domain of collagen type X expression"

"The C4st1 gene encodes chondroitin 4-sulphotransferase-1, which catalyses the sulphation at the 4-0 position of chondroitin and dermatan sulphate. Homozygous mice lacking the transmembrane and intra-Golgi catalytic domains of this enzyme display severe dwarfism and neonatal death"

"Nkx3/Bapx1 inhibits Runx2 expression and chondrocyte hypertrophy, and appears to be a mediator of the actions of PTHrP "

"Chondrocytes in developing bones of Mef2c-null mice fail to undergo hypertrophy; moreover, they fail to express Runx2, indicating that MEF2C acts upstream of Runx2 in the induction of chondrocyte hypertrophy. Chondrocytes from Mef2c-null mice also fail to express Col10a1, which is a direct transcriptional target of MEF2C. MEF2C and HDAC4 exert antagonistic effects on chondrocyte maturation."

"In most larger mammals (but not in rodents), blood vessels within cartilage canals provide nutrients to growth cartilage"<-This could lead to different effects between LSJL on mice and humans.

"Cathepsin L-null mice have defective metaphyseal ossification, but the cellular defect appears to be a lack of osteoclasts"

"FGF18 induces Vegf expression in chondrocytes, and in Fgf18-null mice, in which vascular invasion is delayed, Vegf expression in hypertrophic chondrocytes is reduced"


Development of the endochondral skeleton.

"Endochondral bone development begins with the condensation of mesenchymal cells of either neural crest in the craniofacial region (e.g., middle ear bones and temporal bones) or mesoderm elsewhere in the body"

"In the limb bud the condensation forms mainly through active congregation of cells without changes in cell proliferation. These condensations can be visualized by the dense packing of cells, the high affinity to the lectin peanut agglutinin, and the transient up-regulation of versican, tenascin, syndecan, N-CAM, and N-cadherin"

"BMP signaling was required for the coalescence of smaller aggregates into a tight cluster with a distinct outer boundary, a prerequisite step for chondrogenic differentiation. This event occurred independently of SOX9, because Sox9-null cells can coalesce, even though they subsequently segregate from the condensations and adopt a distinctive “fibroblastoid” morphology."

"SOX9 is dispensable for the initial formation, but necessary for maintaining the condensation."

"inactivation of both FGFRs 1 and 2 in the limb bud mesenchyme (with Prx1-Cre) results in smaller skeletal elements."

"In chick embryonic limbs and limb bud micromass cultures, ectopic expression of WNT1 or WNT7A inhibited chondrocyte differentiation but did not affect formation of mesenchymal condensations"

"The antichondrogenic role of WNT proteins may be mediated through β-catenin, as overexpression of a stabilized form of β-catenin in mouse embryonic limb mesenchyme resulted in a near complete loss of all limb cartilage elements. Continued exposure to WNT/β-catenin signaling appears to redirect limb mesenchymal cells to the soft connective tissue, but this process can be prevented by FGF signaling. WNT/β-catenin signaling also has further inhibitory action at stages after Col2a1 expression has been activated. Conditional overexpression of a stabilized β-catenin by Col2a1-Cre can lead to severe achondrodysplasia"

"Depicted is a longitudinal section through one of two growth plates of a mouse long bone during late embryogenesis (E15.5–E19). The growth plate at this stage is without a secondary ossification center and is organized into distinct domains as indicated. (1) IHH and PTHrP coordinate chondrocyte proliferation and maturation through a negative-feedback mechanism. IHH produced by pre- and early hypertrophic chondrocytes stimulates chondrocyte proliferation and PTHrP transcription through derepression of GLI3. PTHrP in turn suppresses chondrocyte maturation associated with IHH expression. Direct IHH signaling also regulates the formation of columnar chondrocytes from round chondrocytes (not depicted here). (2) FGF9/18 from the perichondrium suppresses chondrocyte proliferation and maturation. FGFR3 expressed in chondrocytes is a likely receptor for FGF9/18 to suppress proliferation in the growth plate late in embryonic development and during postnatal bone growth. FGF9/18 may use other yet-to-be-established mechanisms to suppress chondrocyte maturation in the early embryo. (3) BMPs expressed by both chondrocytes and perichondrial cells promote proliferation and maturation. (4) NOTCH signaling in chondrocytes promotes proliferation and maturation. (5) WNT5A expressed by prehypertrophic chondrocytes stimulates hypertrophy."

"NOTCH signaling may inhibit both mesenchymal condensation and subsequent chondrocyte differentiation."

"PTHrP appears to delay chondrocyte hypertrophy, mainly by activating cAMP-dependent signaling that both increases the activity of SOX9, and regulates the HDAC4–MEF2C complex"

"Like RUNX2, HDAC4 is expressed in the prehypertrophic and early hypertrophic chondrocytes. Genetic deletion of HDAC4, like overexpression of RUNX2, greatly accelerated chondrocyte hypertrophy. Conversely, overexpression of HDAC4 in all chondrocytes inhibited hypertrophy, mimicking the effect of RUNX2 deletion. Biochemically, HDAC4 physically interacts with RUNX2 and reduces RUNX2 binding to DNA. Thus, HDAC4 prevents premature hypertrophy of chondrocytes in part by directly suppressing RUNX2 activity."

"β-catenin signaling appears to function downstream from IHH, as β-catenin deletion does not impair IHH signaling in the perichondrium (containing osteoblast progenitors), whereas IHH removal abolishes β-catenin signaling in that compartment"

"Whereas RUNX2 deletion leads to a hypoplastic perichondrium, loss of OSX causes ectopic cartilage formation beneath a thickened perichondrium at the midshaft of long bones (where a bone collar normally forms)"

"(TWIST1, HAND2, ZFP521, STAT1, Schnurri 3, GLI3, HOXA2, and the HES/HEY proteins) have been found to suppress RUNX2 levels or activit"

A biochemical strategy for simulation of endochondral and intramembranous ossification.

"PTHrP is expressed in the articular perichondrium and Ihh is expressed in the centre of the hyaline cartilage. In this process, these molecular factors diffuse through the bone, where Ihh reaches its highest value in the distal area and PTHrP in the proximal area. Both Ihh and PTHrP are present throughout the epiphysis, reaching a stable equilibrium to changes in the size and shape of the bone."

"Chondrocytes become HCs when the concentration level of PTHrP is lower than a threshold value. During this time, the cells hypertrophy in the centre of the hyaline cartilage where PTHrP is low."

"During the growth stage, the elongation of the cells from proliferation to hypertrophy generates bone growth, as seen in the linear concentration change of cells. The proliferation in the radial direction in the epiphysis causes growth in the diameter of the femoral head."

"we assume the presence of a reaction–diffusion system of two primary molecules, such as BMP2 and Noggin whose distribution in space may lead to a stable pattern in time and an unstable pattern in space, similar to the differentiation patterns of osteoblasts from mesenchymal cells."

Human Long Bone Development in Vivo: Analysis of the Distal Femoral Epimetaphysis on MR Images of Fetuses.

"272 MR imaging examinations (April 2004-July 2011) in 253 fetuses with a mean gestational age (GA) of 26 weeks 6 days (range, 19 weeks 2 days to 35 weeks 6 days) without known musculoskeletal abnormalities. Two independent readers qualitatively analyzed epiphyseal and metaphyseal shape, secondary ossification, and the perichondrium on 1.5-T echo-planar MR images and correlated the results with the GA that was derived from previous fetal ultrasonography (US). Diaphyseal and epiphyseal morphometric measurements were correlated with GA by means of the Pearson correlation and linear regression. MR imaging measurements of diaphyseal length and US normative values were compared graphically. Interreader agreement analysis was performed with weighted κ statistics and the intraclass correlation coefficient.  With advancing GA, the [cartilagenous] epiphyseal shape changed from spherical to hemispherical with a notch, and the metaphyseal shape changed from flat to clearly undulated. Secondary ossification was not observed until 25 weeks 3 days. The perichondrium decreased from 20 weeks onward. Correlation coefficients were 0.897 for diaphyseal length, 0.738 for epiphyseal length, and 0.801 for epiphyseal width with respect to GA. The range of measurements of diaphyseal length was larger than that of the reported US normative values. Interreader agreement was good for bone morphometrics (intraclass correlation coefficient, 0.906-0.976), and moderate for bone characteristics (weighted κ, 0.448-0.848)."

"there was a significant correlation between the epiphyseal length and width"