This is a study that could have massive ramifications on height increase but the the exact mechanism is unknown.  But that cells that have the genetic material of growth plate cells are retained in adult bone is huge news.

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation.

hypertrophic chondrocytes<-full study

“Chondrocytes and osteoblasts are considered independent lineages derived from a common osteochondroprogenitor. In endochondral bone formation, chondrocytes undergo a series of differentiation steps to form the growth plate, and it generally is accepted that death is the ultimate fate of terminally differentiated hypertrophic chondrocytes (HCs). Osteoblasts, accompanying vascular invasion, lay down endochondral bone to replace cartilage.  [Can] HC become an osteoblast and contribute to the full osteogenic lineage? Here we use a cell-specific tamoxifen-inducible genetic recombination approach to track the fate of murine HCs and show that they can survive the cartilage-to-bone transition and become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. This discovery of a chondrocyte-to-osteoblast lineage continuum revises concepts of the ontogeny of osteoblasts, with implications for the control of bone homeostasis and the interpretation of the underlying pathological bases of bone disorders.”

This is huge because it means that the transdifferentiated osteoblasts retain some of the chondrocytic genetic material which means they could possibly dedifferentiate back into chondrocytes!

“The expression of preosteoblastic markers in LHs before the formation of the POC raises the possibility that these cells may transition to an osteoblastic fate”

“HC-Derived Cells Are Present in Fetal, Neonatal, and Adult Bone.”

“The HC-derived cells, morphologically resembling osteoblasts, were found close to the chondro-osseous junction, on the surface of trabeculae, and in the endosteum”<-that means they are in a good position to be involved in neo growth plate formation.

“HC[hypertrophic chondrocytes] Derivatives Transit to the Primary Spongiosa and Become Col1a1-Expressing Cells.”<-the majority of HC derivatives become osteoblasts.

“HC-to-bone transition occurs during postnatal bone growth and that HC-derived cells may be long-lived within the mature bone”

Here’s an image of the HC lineage:

“The reversion of HCs to a prehypertrophic- like state in response to endoplasmic reticulum (ER) stress suggests that hypertrophy is not an irreversible state in vivo”<-Could we revert HC-derived osteoblasts back to hypertrophic chondrocytes back to pre-hypertrophic cells to reform growth plates.

(Michael: That actually makes a lot of sense if one thought about it. It can’t be all dead inorganic bone ECM matter where the physeal cartilage turns into bones (aka Primary Spongiosa). How would bone cells even be able to travel to that middle-region later on if the chondrocytes completely died out and the lucanae was covered by calcium minerals. For the smooth gradual transition from the hypertrophic layer to the vascularization/calcification layer to the mineralization layers to work out, there would be some minority of chondrocytes which would change identities. If all the chondrocytes died out and the layer of the lucanae was completely mineralized, I would not be sure that osteoblasts would be able to reach the primary spongiosa layer.

Here is what I have found years ago. (Source: Chondrogenesis just ain’t what it used to be) Prehypertrophic chondrocytes secrete IHH while the chondrocytes from the perichondrium secrete PTHrP, which effect the PTH/PTHrP receptors which are on the prehypertrophic chondrocytes. In addition, we have to consider the effects of the VEGF. VEGF is secreted by hypertrophic chondrocytes, and that it acts as a major inducer of vascular invasion.

The big thing is the following…

“…demonstrated that Ihh is not only required for chondrocyte hypertrophy, but also for expression of Cbfa1, a transcription factor required for osteoblast differentiation”

If the molecular biologist researchers have been able to identify all of the  major players which causes the chondrocytes to go into apoptosis, and also transdifferentiation, then we at least know which transcription factors causes the changes. I suspect it is Cbfa1.

Refer also the seminal work “Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development”

That study proved conclusively that it is IHH that starts everything. IHH stimulates the Cbfa1, which causes the vascularization. I am going to make a guess that somewhere along the way, the two peptides also caused the transdifferentiation.

So how do we actually figure out what type of chemical would lead the osteoblast/osteocytes types to go in reverse and de-differentiate aka some type of reverse transdifferentiation?

We first have to assume that there is some type of external stimuli (mechanical, chemical, electrical) which would be able to even do the de-differentiation.

I propose this idea for Tyler…

Let’s assume that if we change the environment, the cell will start to change its identity. Remember the study which showed that the path which the MSCs will differentiate into can be determined by the shape of space that they are placed into? That suggest that if we change the environment that the osteoblasts/bone cells are in, maybe they will change as well.

Here is my first idea: I propose that we try to remove the calcium crystals/de-mineralize the area. To do that, remember that the PTH and the PTHrP balance from the parathyroid glands controls the level of calcium that is dissolved into the human blood (refer to “Chapter 5 – The parathyroid glands and vitamin D“)

“In bone, within 1 or 2 hours, PTH stimulates a process, known as osteolysis, in which calcium in the minute fluid-filled channels (canaliculi/lacunae) is taken up by syncytial processes of osteocytes and transferred to the external surface of the bone and, thence, into the extracellular fluid. Some hours later, it also stimulates resorption of mineralized bone; a process that releases both Ca2+ and Pi into the extracellular fluid. The Pi is rapidly removed from the circulation because the most dramatic effect of PTH on the kidney is to inhibit reabsorption of Pi in the proximal tubule and markedly increase its excretion“

Let’s increase the level of PTHrP in the local region, which is what I had proposed in a post I had written more than a year ago (The Connection Between Regenerating Deer Antlers and The PTHrP, PTH And IHH pathway for Cartilage Regulation, PTHrP Seems To Be The Answer (Big Breakthrough!)). Decrease the concentration of CA2+ from the ECM, and see what happens to the osteoblasts. Would they de-differentiate into chondrocytes if their environment changes?

It might be that the formation of osteoblasts and the increased levels of mineralization/vascularization/calcification is a positive feed back loop where each part feeds upon itself, which is initialized by VEGF. If we break the positive cycle at the process of mineralization, would the osteoblasts also go in reverse?

The Problems From Using Growth Hormone Therapy To Make Growing Children Taller

In a recent post that the heightism blogger Geoffrey Arnold wrote in the r/short subreddit, he made a point on the limitations of growth hormone therapy to treat idiopathic short stature. On a certain level, he is right. However, there is more to the science than just reading the Abstracts to PubMed articles, which I have found many people already do ie. Bodybuilders, and amateur researchers. He is well read, but not at a level of a person who has gone deeper into the details.

I refer to the post…

On his first claim, 99% of the time, he is correct, however there have been certain cases of individuals who did see a slight bit of increase in their adult height after using HGH, but it was almost always just 1 inch or so. I refer to someone actually well known in the online community, one of the founders/spokesperson of the website GoodLookingLoser.com The big muscled guy wrote in one thread that he did grow 1 full inch after he started to take growth hormones for his workouts to increase his muscle size. Many people responded saying that he couldn’t have since he was too old and his growth plates were fused, but he has stuck by his claims.

On his 2nd claim, he is only half right.

The thing is that children who are short statured which is caused by growth hormone deficiency will have a much more pronounced and dramatic boost in growth and final adult height from using growth hormones, but that does NOT mean that developing children with fully open epiphyseal growth plates who are short statured which is NOT caused by GH deficiency won’t see any height increasing results. That is where he is wrong.

The clearest example is to ask the question, for the hundreds (maybe even thousands) of people throughout history who has become giants from pituitary gland GH over-stimulation, did they also suffer from GH deficiency? From a anatomical point of view, radiologists looking at X-Rays and/or MRIs have shown that the pituitary gland have become enlarged, or has a unique tumor in the brain area. When it was found that this chemical called growth hormone was released mainly from the pituitary gland,  the link between cases of gigantism and the extra-stimulation and release of GH was clear.

The real question becomes, for a person to actually develop gigantism, is whether they have to suffer two different conditions simultaneously, 1) having growth hormone deficiency to make them more GH susceptible and 2) then have an overactive pituitary gland to develop into tall stature, or is it just an overactive pituitary gland?

I would guess the latter. Increased levels of GH that is coursing through the developing child’s system will make them bigger.

Now, the claims made are backed by studies, like the 2007 article “Growth Hormone Injections Add Height, But Kids Stay Short” In that article, it makes it seems like certain children are just destined to be short, and not even GH therapy would help them. The expensive, weekly injections would only give around 3 inches of extra height. The amount of money needed is stated to be around “Each half-inch in final height gained via human growth hormone therapy costs anywhere from $18,000 to $36,600“

Jackie Bryant, did make the point that even with with GH therapy, kids with idiopathic short stature would still be relatively short. However, we like to point out the word “relatively“. If Geoffrey took the time to look at the real data for the studies, he would see that technically the GH injections did make developing children taller, but maybe not as much as to change the fact that those children will not be the next Shaq.

We quote the article…

“Despite these findings, children treated with growth hormone remained short near the lower range of normal when compared to their peers.

“Genetic factors affect growth and final height, and parents should be realistic in their expectations about the potential effects of growth hormone,” Bryant said“

If a kid is only 4 feet tall and started to use GH on a weekly basis starting at 13, they are not going to be 6 feet tall by the time they are 18.

(Reference: Bryant J, Baxter L, Cave CB, Milne R. Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004440. DOI: 10.1002/14651858.CD004440.pub2)

The other big problem with GH which we agree with is that to much GH can actually accelerate the bone age and bone maturity, so that the children will have fused growth plates earlier. Growth Plate Senescence does accelerate due to GH therapy usage.

However, that is the main thing. Arnold said that GH Therapy would not even work on children, unless they have GH deficiency. That is not exactly true. Even if a child is not GH deficient, they will get some level of height increase from the years of GH therapy when they are still growing, even though it may be just an extra 1 inch of height.

When it comes to the science of auxology, Geoffrey Arnold is not that well informed on the exact specifics. Please, for the future talk about the sociological, psychological, and anthropological aspects of height, short stature, and heightism, but stay away from the hard sciences, unless one has the right type of educational (or research) background to talk about such issues.

You would make mistakes informing the readers on the wrong things and pushing them in the wrong directions. If we made a mistake, we would be sure to let it be known and correct ourselves and change our opinions and positions on whatever matters we are discussing.