One group of growth factors which seem to really come up a lot in the research besides the bone morphogenetic proteins (BMPs) are the Growth Differentiation Factors (GDFs). The GDFs in general a a sub-group of the larger TGF-Beta superfamily of growth factors which have some role in development with around 30 combined total elements found so far.

In the past we saw that some GDFS, like GDF-5 and GDF-2 seem to have pro chondrogenic properties. From the wikipedia article on Growth Differentiation Factors I find that there is a GDF 1, 2, 3, 5, 6, 8, 9, 10, 11, and 15. Of the chart in the article, I would guess that the GDF2,3,5, and 10 are the most important ones for bone formation and development so these will be the only GDFs I will be focusing and doing any type of research on for the post. GDF2 is also known as BMP-9, GDF3 is also known as VGR-2, GDF10 is also known as BMP-3b.

---

GDF-5

From the R&D Systems website I would learn further about the functions and nature of the GDF-5…

“…It can be secreted by precartilagenous mesenchymal condensations involved in the formation of digits. It is also produced by fibroblasts, articular cartilage chondrocytes, and odontoblasts. GDF-5 actions may be mediated by the TGF-beta superfamily receptors ALK-6, BMP-RII, or Act-RII.“

This would suggest that it is secreted in the earlier stages of pre-natal embryo and fetal development since the fingers and toes are grown from their release. As for the fibroblasts and the articular cartilage chondrocytes, it shows that the GDF probably has not just some bone cell function, but also cartilage cell function. From the Medical Dictionary website I would learn that odontoblasts are “one of the connective tissue cells that deposit dentin and form the outer surface of the dental pulp”

The R&D Systems website would be more helpful in explaining the importance and influence of at least the GDF-5…

“The majority of GDF-5 research has centered on embryogenesis and on the development of joints in particular. GDF-5 has an apparent role in the formation of some synovial joints of the digits. GDF-5 may contribute to the formation of the early cartilage mass by promoting mesenchymal transformation to cartilage”

This suggest that while the entire array of functions of GDF-5 may not have been completely discovered, there is a lot of evidence in showing the link between GDF-5 and the development of joints. It seems that the synovial joints require this growth factor. At least for embryos and developing fetuses, the GDF-5 seems to be get the initial cartilage to form from mesenchymal stem cells. For our height increase interest, this shows that maybe it is possible still for fully mature grown up adults to get GDF-5 into their bone marrow to cause some cartilage formation as well.

Further on…

“Finally, after formation of the synovial cavity (see Figure 1c), GDF-5 may direct tendon and ligament formation around the joint, and induce cartilage expansion (thus bone lengthening) in the residual cartilage of bones associated with the synovial joint”

This shows that the GDF-5 has a way of directing the direction and arrangement of other tissue formation and postioning around the synovial joint, which it also has a influence on development on. It may appear that it would be the GDF-5 that is the real growth factor cause for endochondral ossification in the first place. The sentence suggest directly that the entire reason the cartilage even expands in the first place is from the action of GDF-5.

---

GDF-3

From a database on the National Institute Of Health website as a summary it states…

“The protein encoded by this gene is a member of the bone morphogenetic protein (BMP) family and the TGF-beta superfamily. This group of proteins is characterized by a polybasic proteolytic processing site which is cleaved to produce a mature protein containing seven conserved cysteine residues. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues.”

The summary is not that useful but as for function I refer to the study “Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.” The study suggest that the GDF-3 has at least some involvement in the development in some of the eye parts. When the GDF-3 creating gene is removed from tested animals, there is clear signs of development maladies. From paper “GDF6, a novel locus for a spectrum of ocular developmental anomalies.” it would seem that the GDF-6 besides the GDF-3 also has a role in ocular development.

From paper “Growth differentiation factor 3 is induced by bone morphogenetic protein 6 (BMP-6) and BMP-7 and increases luteinizing hormone receptor messenger RNA expression in human granulosa cells.” I would learn that it is possible to induce GDF-3 with BMP-6 or BMP-7 and that it has an inhibitory effect on the BMP cytokines. This idea would by validated by paper “GDF3, a BMP inhibitor, regulates cell fate in stem cells and early embryos.” What is startling from the short abstract is to learn that in both mouse and human stem cells, the GDF-3 is expressed a lot by the stem cells in pluripotent form. The conclusion give us another clue on maybe how to reverse or at least hold off on the differentiation process of stem cells so we can control how it changes over time.

“Furthermore, we use gain- and reduction-of-function to show that in a species-specific manner, GDF3 regulates both of the two major characteristics of embryonic stem cells: the ability to maintain the undifferentiated state and the ability to differentiate into the full spectrum of cell types.”

From paper “GDF3 at the crossroads of TGF-beta signaling.” we again see that the GDF-3 has a huge influence on undifferentiated embryonic stem cells which are still pluripotent in nature. The researchers conclude with “Chen and colleagues found that GDF-3 acts as a nodal-like TGF-beta ligand. These combined findings raise the intriguing possibility that GDF-3 acts as a bi-functional protein, to regulate the balance between the two modes of TGF-beta signaling.”

This raises the point that it seems to both help and inhibit many different types of growth factors in the TGF-Beta superfamily. It regulates a balance, so it can get the TGF-Beta groups to either increase or decrease. Like the GDF-5, it is becoming more and more clear that it has a huge influence on very early development and can be one of the keys to determining whether one’s height will be tall or short.

---

GDF-2

As for the sub-unit the growth differentiation factor 2, aka BMP-9 I used the source Wikigenes to get my information. From the sources posted it does seem that the GDF-2 aka BMP-9 has some chondrogenesis abilities. It also has some osteogenic abilities since rats bred without the GDF-2 encoded gene did inhibit some osteogenic development problems.

---

GDF-10

From the list of GDF-s on the original wikipedia chart, I have decided only to research and evaluate the research importance of GDF-5, 2, 3, and 10 since they seem to have some roles and involvement in the bones and cartilage development. Many of the other GDFs are involved in neuron or muscular development. For the GDF-10 element, again I would use its Wikigenes profile page as the only source for reference. It looks credible and well researched, even if the creation of the page did not involve combing through every single PubMed study ever linked or mentions the GDF-10 sub-unit. The GDF-10 seems to be very much related to the BMP-3 so it is also named BMP-3b.

The first major claim made by the site is during embryogenesis the GDF-10 has a role in formation of the bones in the skull and the vertebrate. As for the biological context of the GDF-10 we find that it has multiple roles in the cell differentiation for the formation of the skeletal structure. The mRNA for it is found in both prenatal and post natal individual’s bones.

There is a 2nd Wikigenes page on the GDF-10 where more genetic related information is found which I didn’t go through.

GDF-9

There is a Wikigenes page for GDF-9. From some studies off of PudMed HERE I would learn that the GDF-9 has function in female ovary, non mature egg development. They are secreted by oocytes in growing ovarian follicles.

From a paper on GDF-9 “Growth differentiation factor-9 is required during early ovarian folliculogenesis”  I would learn that at least one of the functions of the GDF-9 is required for ovarian folliculogenesis. The researchers conclude their abstract with…”GDF-9 is the first oocyte-derived growth factor required for somatic cell function in vivo.”

It would seem that even with its Wikipedia article, there is no mention of any development with bones or cartilage

---

Conclusion:

Overall the entire group of Growth Differentiation Factors has a major influence on the development process of every single type of cell in the body. It has been rather difficult in being able to separate and identify the specific GDF types which only focus on the development of either the bone or cartilage. Most of the GDFs have multiple functions.

However there are some studies which show that at least one of the GDF really has a direct influence on endochondral ossification and human growth. From the paper “Mechanisms of GDF-5 action during skeletal development” we would learn that transgenic mice that has their ability to recieve GDF removed showed many different types of genetic disorders of the limbs including chondrodysplasia. There is shortening of the appendicular skeleton and also either no or abnormal development of the joints. From Wikipedia I would learn that the term “appendicular skeleton” actually refers to the bones that make up the limbs aka appendages. This means all the bones in the torso, neck , and head are not part of the appendicular skeleton. The researchers decided to test to see how important the GDF-5 is in skeletal development. They took young chickens and overexpressed the gene that makes this protein. The result is that the overall skeletal length or amount of skeleton increased by 37.5% which is contributed to increases in the number of chondrocytes. For this nearly amazing growth factor, the researchers say it can do all these functions.

GDF-5 can…

• Increase the size of the early cartilage condensation and the later developing skeletal element
• Increases chondrogenesis in a dose-dependent manner.
• Might act at these stages by increasing cell adhesion, a critical determinant of early chondrogenesis
• At later stages of skeletal development GDF-5 can increase proliferation of chondrocytes
• In controlling the size of skeletal elements and provides a possible explanation for the variation in the severity of skeletal defects resulting from mutations in GDF-5.

At this point I am going to focus almost all of my research on the Growth Differentiation Factors on the GDF-5 and a little on GDF-3. What I might even suggest at this stage is that the GDF-5 may be one of the most critical elements in our research.