A Viable, Real Method To Stop Growth Plates From Closing By Inhibiting Chondrocyte Mineralization and Epiphyseal Cartilage Neovascularization – Breakthrough!

Recent searching through the Google Patent Database revealed a few patents which have been filed which pertains to our goals.

The most important patent is a couple of researchers from Columbia University, Jie Jiang and Helen Lu entitled “Methods for inhibiting cartilage mineralization – WO 2008156725 A2″.

What makes this patent so unique and special is that the chemical that is proposed for injection to the locallized area is a chemical which I have written before multiple times and theorized was the key to possible bone interstitial growth even after bone maturity. – “Parathyroid Hormone And Parathyroid Hormone-Related Protein May Lead To Non-Invasive Epiphyseal Growth Plate Regeneration (Big Breakthrough)”.

Of course that post was written in late 2012, which was only the very start of my research. It seems that this patent which was filed back in 2008 seems to validate this idea that using Parathyroid Hormone-Related Protein (PTHrP) would have inhibitory effects on the mineralization process on chondrocytes in hyaline cartilage.

Here is what is important to realize. This patent technically talks about using PTHrP on articular cartilage. The fact that two researchers from a leading research university is willing to put 5,000K USD to file a patent for this idea shows that the science is real. They thought the idea was viable enough to get a patent on it. So I would say it is reasonable to assume that using PTHrP on the articular cartilage will prevent the chondrocytes from mineralization.

Scientifically speaking, when you do the research on looking at how IHH (Indian Hedgehog) controls the rate of stimulation of PTHrP in the profeliferation and hypertrophic layers of the growth plate, it might cause the more discriminatory researcher to suggest that maybe IHH, not PTHrP should be the chemical we should focus on. Technically, it is true that IHH is the chemical that will cause PThrP to be stimulated. There is a negative feedback look in the layer of the growth plate. If the PTHrP chemical is stimulated, it tells the levels of IHH to drop, like a sort of check system to make sure the chemical process doesn’t turn into a run-away chemical reaction chain. However, from what I remember, it is PTHrP that is what actually causes the type of chondrocyte actions that we wants, specifically increased proliferation and then increased hypertrophy. In addition, I seem to remember vaguely at least 1 study which says that increased PTHrP seems to prevent the hypertrophic chondrocytes from undergoing apoptosis too quickly.

This is why I believe that this patent (or method/technique) can be translated to the application of inhibiting chondrocyte mineralization also in the epiphyseal cartilage layers.

If you read the patent and dig into the details, the inventors mention that there is at least half a dozen ways to get the PTHrP to be administered to the deep zone layer of articular cartilage. if there is a half different way to get the chemical to reach the end of the bones/ epiphysis, then there is probably the same number of ways to reach a growth plate that is still not fully closed.

To further validate this idea, there was also another patent filed by a completely different research team based in China on the same idea. You inject PTHrP to stop early onset osteoarthritis.  Refer to the patent # “Treatment of early-stage osteoarthritis
US 8586533 B2″. For this particular 2nd patent, they prefer the intra-articular injection method. Also, for the exact amount of PTHrP used, they suggest within the range of from about 0.1 nM to about 200 nM in the synovial fluid of the synovial joint. 

What is even more amazing is that fact that we don’t even need to use this organic protein alone to inhibit chondrocyte mineralization.

Refer to the studies below.

Here are the other chemicals to stimulate. – TFG-Beta1, Glutamate, and Vitamin C Sulfate.

Here are the chemicals to decrease – Annexin V

So theoretically, would injection of a TGF-Beta1 and PTHrP combination into the layer of growth plates work in stopping the growth plates from completely closing up?

Of course, no chemical is good enough to completely inhibit the process of epiphyseal fusion. I forget which study I read (involving Sox9) which explained in extremely fine detail what was the exact chronological steps for the chondrocytes to die and have the remaining area turned into osteoblastic tissue.

The first step I believe was that the hypertrophic chondrocytes had something activated to cause them to secrete the chemical alkaline phosphatase (ALP). The waste that is expelled by the chondrocyte which had expression levels of ALP in it caused the area to become vascularized. Once the area becomes vascularized, then it become mineralized. Certainly mineralization is one of the key steps in this multi-step process. Then there are maybe 4-5 other steps after this, but we are not going to focus on those steps. In any series of chemical reactions, the easiest way to stop the series of reactions is to stop the first reaction from happening, thereby nipping the entire thing at the bud.

The idea that if we can just inhibit this one step, the mineralization step, means that the overall ECM still stay elastic and not bone hard. It may still go through the step of neo-vascularization become vascularized, and it may cause a run-away reaction of all the chondrocytes going through apoptosis but the matrix should stay in a cartilage-type tissue form for a much longer time. This would give the overall structure to possibly more time to expand longitudinally, thus making the bones longer than if they went their normal rate.

In conclusion we might consider the idea of also using Chondromodulin Type I or Type II, as well as GDF-5 in combination ,to possibly stop the vascularization as well.

If we stop both the mineralization and the vascularization, then we would stop the growth plate from ever closing, if we can figure out how to stop the hypertrophic chondrocytes from expression ALP through their waste.

{Tyler-Note that just because mineralization of the growth plates ceases does not mean that height will increase.  Stopping growth mineralization does not stop growth plate senescence see mice and rats.  Also, slowing down mineralization has been shown to decrease height in some instances.  It’s possible that it could increase height but experiments would be needed to test.  The better strategy is to stop growth plate senescence._