Some that may be perplexing for any real height increase researcher is to wonder…

“Why Does The Epiphyseal Cartilage Disappear And The Articular Cartilage Remain? Aren’t they getting the same amount of load?”

This was a huge question I started to ask myself and I think the search to answer this critical question lead me to one of the biggest discoveries in quite a long time. I would be directed to a paper which I had previous cited before in the post “Theories On Delaying Puberty To Extend The Growth Period”

It is entitled “What Makes the Permanent Articular Cartilage Permanent?” which is not a real scientific study or article but onyl an editorial. However the information inside this 2 and a half page editorial really does shed light on something that has been on my mind.

What makes the articular cartilage special?

Analysis & Interpretation:

This will be my first attempt at trying to summarize my readings without trying to copy an entire abstract or the article. At this point I think that most readers don’t really care about the technical details. They are looking for the answer to their height increase solutions but are hoping that height increase researchers like me will do the hard scientific theory and research for them. And that is cool. I like learning about this stuff.

So for this post, when I am talking about the articular cartilage, I am talking about say the stuff that an orthopaedic surgeon would find at the distal end of the femur  when they open up the knee area and see what is there. I am really just going to look at the articular cartilage for one very special area in the body, in the knees, for the distal femur end the proximal tibia end, which are the two epiphysis ends that come together to make the synovial knee joint.

What I learn is that the articular cartilage, like all cartilage is a type of connective tissue. The tissue is not jammed with small cells in some organized fashion like some cells. There is the extracellular matrix of the articular cartilage and the chondrocytes inside. The matrix is rather hard in material strength. It covers the bones so that the bones themselves don’t touch, cause friction, and cause that local area in the body to become inflammed. The chondrocytes inside are kept safe by the matrix. They don’t so through hypertrophy (aka expand in volumetric size) like the chondrocytes you find in the epiphyseal cartilage and the chondrocytes are not enveloped by blood vessels since the cartilage seems to be able to protect itself from vascularization. Let’s remember from many of our previous research that vascularization for the epiphyseal cartilage is a bad thing for our desire to continue to grow longitudinally.

The articular cartilage manages to keep the cartilage phenotype around, preventing the intrusion of blood vessels from getting in. How is this done? The complete mechanism is not really known but in the last few years new evidence has been coming out to make a suggestion on what could be the cause. The writer notes that it seems that the usual suspects for growth factors like the TGF-Beta, BMPs, and the FGFs are produced in by the chondrocytes in the articular cartilage but not in the high level of amount that would be expected to say keep the cartilage and the chondrocytes alive. The real element that seems to keep the cartilage around, which a researcher named Klinger discovered was the angiogenesis inhibitor Chondromodulin Type-1. The matrix protein Chondromodulin Type-1 when used in lab pigs for testing showed that if Chondromodulin Type-1 is over expressed then cartilage will not get vascularized or ossified as quickly than cartilage which has little Chondromodulin Type 1. The results were shocking. The cartilage resisted calcification and vascularization for 6 months.

The administering of Chondromodulin was done two ways on cartilage defects…

1. either through the gene therapy method, which was to put the Chondromulin Type 1 complementary DNA into a vector and put the vector into cells which are pregenitors before they either differentiate into either chondrocytes or osteocytes. The chondorcytes then would overexpress on the chondromodulin protein in their production. The chondrocytes are then implanted in the defect area.

2. Or the vector without the cells is directly put in the defect.

From an in vitro context it seems that the Chondromodulin Type 1 has shown no effect in terms of overexpression of VEGF from looking at mRNA levels, but Klinger and the other researchers do note that they are looking at the process of the effects of Chondromodulin in a rather simplified system and that the effects of Chondromodulin in vivo can be more complex. They would also suggest that the matrix protein is something else that can prevent chondrocyte hypertrophy from blocking the expression of Collagen Type X, which is the type of collagen hypertrophic chondrocytes releases and is detected from histological testing.

The researchers would also ask whether Chondromodulin Type 1 is what can cause the down-regulation or inhibit the expression of  runt-related transcription factor 2 aka RUNX-2. The reason for this idea to check the effects on RUNX-2 is that RUNX-2 is one of the compounds that seems to regulate the production and/or expression of Collagen Type X and also VEGF type A

The researchers note that SOX9 should also be investigated. The SOX9 gene has been shown to be involved in the beginning stages of cartilage development. It seems that SOX9 is downregulated in the chondrocytes that are in hypertrophy in the growth plate during ossification. The authors of the study notes that another group  of researchers managed to show that SOX9 is very important in preventing the vascularization and endochondral ossification when just the hypertrophic chondrocytes were examined. The researchers state…

“Furthermore, they showed by in situ hybridization and real-time polymerase chain reaction that Vegfa, Mmp13, and osteopontin were all down-regulated in hypertrophic chondrocytes that misexpress Sox9, thus indicating that terminal differentiation was inhibited. Vegfa was also shown to be negatively regulated by direct binding of Sox9 to the Vegfa promoter”

It seems that the key original gene is the SOX9 gene which regulates the Chondromodulin Type 1. From looking at young chickens it is noted that both the SOX9 protein made by the Sox9 gene and Chondromodulin Type 1 are usually found in the same region in the body where there is no vascularization, ossification, and the cartilage stays around. From looking at studies with hearts, the same thing is found where the Sox9 expression seems to prevent heart tissue from becoming calcified. The exact heart part are the valves, which turn out not be heart tissue, but more cartilagenous in nature. The valves don’t seem to get vascularized which might turn them too rigid or hard to be flexible enough to deal with the rigorous demands of constant use in the human body.

Note what the researchers state below…

“Hence, chondromodulin 1 is most likely indirectly up-regulated by hypoxia, i.e., via SOX9, which is up-regulated under hypoxic conditions by hypoxia-inducible factor 2. Whether SOX9 directly binds and regulates chondromodulin 1 is an important unresolved question. However, this pathway provides one plausible mechanism by which this avascular tissue maintains its function throughout life, i.e., the chronic hypoxia in the cartilage helps maintain SOX9 expression levels that prevent vascular invasion (through, e.g., chondromodulin 1 induction) in addition to direct inhibition of terminal differentiation and subsequent calcification of the tissue as occurs, for example, in the murine growth plate when Sox9 levels greatly decrease prior to hypertrophy”

So it seems that this pathway guessed by this writer is

no blood vessels —> blood and O2 molecule never reaches the cartilage –> SOX9 is up-regulated –> Chondromoduline Type 1 is upregulated –> The Chondromodulin and Sox9 protein both prevents any vascularization/blood vessels from ever reaching into the articular cartilage, calcifying and ossifying it –> this continues through life as a positive feedback loop keeping the cartilage avascular.

We find that PTHrP (Parathyroid Hormone related Protein) seems to increase when chondrocytes in some medium when subjected to mechanical loading. The main thing to remember is that in articular cartilage, the chondorcytes inside are prevented from ever going through the differentiation process of hypertrophy and also prevent the process of vascularization

Implications For Height Increase:

This has shown finally what is the exact main difference between the epiphyseal cartilage and the articular cartilage. There seems to be a  greater amount of over expression of Chondromodulin Type 1 and Sox9 gene expression in the chondrocytes of the articular cartilage than the epiphyseal cartilage. Yes they are both hyaline cartilage but there is some difference in them. The Sox9 seems to either directly or indirectly regulate the Chondromodulin Type I production and they prevent the cartilage from becoming vascularized. Vascularized is the process of getting filled with blood vessels. Vascularization is what seems to lead to calcification and calcification is basically the process that kills off cartilages. They also might seem to prevent hypertrophy. We know that hypertrophy is needed for actual long bone endochondral ossification lengthening since the rate of bone longitudinal increase is positively correlated to the amount of hypertrophy the chondrocytes in the hypertrophic zone can go through (aka the bigger the better). We still need hypertrophy and some vascularization and then calcification of empty pockets to actually make us grow taller when we are still in the natural growing process. However we will need to realize that there will come a point in a person’s development where it will be needed to stop further vascularization and calcification to extend the amount of time for growth by keeping the epiphyseal plate cartilage still around, allowing for another method or technique to come in to add more mesenchyme or chondroprogenitor cells back into the reserve zone so that we can continue the bone lengthening more than it was naturally designed to go through.