Monday, November 1, 2010

Increasing Load to restore Height Gain

The proposed mechanism for Lateral Synovial Joint Loading is by mechanotransduction which is triggered by changes in interstitial fluid flow detected by the actin cytoskeleton.  Many cell types have an actin cytoskeleton to detect changes in load including stem cells.

Cartilage Stem Cells: Regulation of Differentiation
"The developing limb bud is a useful source of cartilage stem cells for studies on the regulation of chondrogenesis. In high density cultures these cells can progress through all stages of chondrogenesis to produce mineralized hypertrophic cartilage. If the cells are maintained in a spherical shape, single stem cells can progress through a similar sequence. The actin cytoskeleton is implicated in the regulation of chondrogenesis since conditions that favor its disruption promote chondrogenesis and conditions that favor actin assembly inhibit chondrogenesis. Since a number of extracellular matrix receptors mediate effects of the extracellular matrix on cytoskeletal organization and some of these receptors are developmentally regulated, it is proposed that matrix receptor expression plays a central role in the divergence of connective tissue cells during development."
So during development a disruption in the actin cytoskeleton by a means such as LSJL induced interstitial fluid flow may promote chondrogenesis.  It may also help increase height in adults by favoring stem cells differentiating into chondrocytes rather than osteoblasts.  A decrease in mechanosensativity may result in a need for a greater amount of fluid flow to induce a disruption in the actin cytoskeleton.  By altering the sensitivity of the actin cytoskeleton to fluid flow we can predispose the cells of the body to a lineage that will result in height increase(chondrocytes).

Micromechanically based poroelastic modeling of fluid flow in Haversian bone.

"To explore the hypothesis that load-induced fluid flow in bone is a mechano-transduction mechanism in bone adaptation, unit cell micro-mechanical techniques are used to relate the microstructure of Haversian cortical bone to its effective poroelastic properties. Computational poroelastic models are then applied to compute in vitro Haversian fluid flows in a prismatic specimen of cortical bone during harmonic bending excitations over the frequency range of 10(0) to 10(6) Hz. At each frequency considered, the steady state harmonic response of the poroelastic bone specimen is computed using complex frequency-domain finite element analysis. At the higher frequencies considered, the breakdown of Poisueille flow in Haversian canals is modeled by introduction of a complex fluid viscosity. Peak bone fluid pressures are found to increase linearly with loading frequency in proportion to peak bone stress up to frequencies of approximately 10 kHz. Haversian fluid shear stresses are found to increase linearly with excitation frequency and loading magnitude up until the breakdown of Poisueille flow. Tan delta values associated with the energy dissipated by load-induced fluid flow are also compared with values measured experimentally in a concurrent broadband spectral analysis of bone. The computational models indicate that fluid shear stresses and fluid pressures in the Haversian system could, under physiologically realistic loading, easily reach the level of a few Pascals, which have been shown in other works to elicit cell responses in vitro."

This article says it's easy to generate the kind of frequencies to generate the fluid flow needed to generate cell responses.  However, they don't study the responsiveness of cells over time...  So if mechanosensitivity is reduced then we nead to increase the fluid shear stresses by using heavier dumbells or more intensity of the table clamp but not too much as to cause the stoppage of flow due to too high pressure or breaking of the bone.

Fluid shear stress inhibits TNFalpha-induced osteocyte apoptosis.

"Bone tissue can adapt to orthodontic load. Mechanosensing in bone is primarily a task for the osteocytes, which translate the canalicular flow resulting from bone loading into osteoclast and osteoblast recruiting signals. Apoptotic osteocytes attract osteoclasts, and inhibition of osteocyte apoptosis can therefore affect bone remodeling. Since TNF-alpha is a pro-inflammatory cytokine with apoptotic potency, and elevated levels are found in the gingival sulcus during orthodontic tooth movement, we investigated if mechanical loading by pulsating fluid flow affects TNF-alpha-induced apoptosis in chicken osteocytes, osteoblasts, and periosteal fibroblasts. During fluid stasis, TNF-alpha increased apoptosis by more than two-fold in both osteocytes and osteoblasts, but not in periosteal fibroblasts. One-hour pulsating fluid flow (0.70 +/- 0.30 Pa, 5 Hz) inhibited (-25%) TNF-alpha-induced apoptosis in osteocytes, but not in osteoblasts or periosteal fibroblasts, suggesting a key regulatory role for osteocyte apoptosis in bone remodeling after the application of an orthodontic load."

By the gene expression analysis of LSJL we already know that LSJL inhibits TNF-alpha.  TNF-alpha also stimulates apoptosis in chondrocytes, so TNF-alpha could cause apoptosis in growth plate chondrocytes or prevent the formation of a new growth plate by new chondrocytes.

Induction of apoptosis in chondrocytes by tumor necrosis factor-alpha.

"Tumor necrosis factor alpha (TNF-alpha) induces apoptosis in a number of cell types and plays an essential role in bone remodeling, both stimulating the proliferation of osteoblasts and activating osteoclasts. During endochondral ossification, apoptosis of chondrocytes occurs concurrently with new bone formation and the resorption and replacement of mineralized cartilage with woven bone. In the present study, the role of TNF-alpha in promoting chondrocyte apoptosis was examined. Chondrocyte cell populations, enriched in either hypertrophic or non-hypertrophic cells, were isolated from the cephalic and caudal portions of 17-day chick embryo sterna, respectively, and treated in vitro with 0.1-10 nM recombinant human TNF-alpha. As a positive control, apoptosis was also induced by Fas receptor antibody binding. Dye exclusion assays of the live/dead ratios of cells showed that TNF-alpha caused a dose-dependent 1.5- and 2.0-fold increase in the number of dead cells in both hypertrophic and non-hypertrophic chondrocytes. Induction of apoptosis was independently assayed by measurement of interleukin-1beta-converting enzyme (ICE) activity, and analyzed by a semi-quantitative determination of DNA fragmentation. When compared to untreated cells, these analyses also showed dose-dependent increases in TNF-alpha induced apoptosis in both chondrocyte populations, with increases in the levels of ICE activity for all doses of TNF-alpha (from approximately 5 to approximately 20 fold). Osteoblasts, however, were not affected by treatment with TNF-alpha or by Fas antibody/protein G induction. Immunostaining of chondrocytes for Fas receptor and caspase-2 protein expression showed that most of the chondrocytes expressed these two markers of apoptosis after treatment with TNF-alpha. Although cell killing and ICE induction were higher in the more hypertrophic cells, TNF-alpha induced apoptosis in both hypertrophic and non-hypertrophic chondrocyte populations. These results demonstrate that apoptosis may be induced in both hypertrophic and non-hypertrophic chondrocytes through both Fas and TNF-alpha receptor mediated signaling, and suggest that chondrocytes are more sensitive to apoptotic effects of TNF-alpha within the skeletal lineage than are osteoblasts."

Inhibiting TNF-alpha and in turn LSJL can increase height in children by reducing apoptosis of chondrocytes.

So until we found a way to increase mechanosensativity, the best solution seems to be to increase load which increases fluid flow.

Another possibility is that in response to LSJL, bone density increases greatly reducing bone porosity making it harder for fluid to flow through bone but in turn one would think that a higher bone density would increase the pressure making it even easier to generate sufficient interstitial fluid flow.  So the reduction in response is likely due to changes in the actin cytoskeleton(actin cytoskeleton remodeling).

We need to identify chemical and physical factors that result in the deconditioning of the actin cytoskeleton to load.


  1. Would it be beneficial to start taking Niacin and Melatonin alongside LSJL at age 20? If so, what size dose and what are your opinions on the combination?

  2. Is there a book/article that could get me into understanding the basics of height growth and bone length increasing?