Tuesday, July 3, 2012

Parathyroid hormone to treat achondroplasia? Part 1

FGFR3 in bone growth
Bone growth is the result of the interaction of a large number of proteins and related molecules that either work accelerating the growth speed or reducing it (Mackie EJ et al. 2011). In achondroplasia, there is one only problem taking place: one of the main speed reducers, the protein called fibroblast growth factor receptor type 3 (FGFR3), is working excessively and impairing the overall bone growth, leading to the clinical aspects of this bone chondrodysplasia (chondro = cartilage; dysplasia = ill formation, or ill formation of the cartilage). FGFR3 is working too much due to a single switch of amino acids in its molecular structure, caused by a corresponding change of a single nucleotide in the FGFR3 gene (reviewed here).
FGFR3 was identified as the agent causing achondroplasia back in 1994 (folllow this link for one of the first papers about it). Since then, much has been learned about how it exerts its effects in the growth plate cartilage (Foldynova-Trantirkova S et al., 2012). This means that the chemical cascade regulated by FGFR3 (reviewed here) is already reasonably known. In summary, FGFR3 works in two ways:
1. Reducing the proliferation of the chondrocytes, the cells within the growth plate cartilage responsible for the construction of the cartilage scaffold that will be replaced by bone tissue;
2. Interfering with the chondrocyte transition to the hypertrophic state (maturation).
The consequence of these two effects is that with fewer cells producing the scaffold, less bone tissue will be created, resulting in shorter and narrower bones.
The best way to reach point B from point A is a straight line but, if there is an obstacle on the road, look for other options
When you want to treat a specific clinical condition, the best strategy would be to interfere directly with the causing agent. However, this is not always possible (not yet, for much science advance is still needed to accomplish that) so doctors may prescribe medicines that interfere in known chemical reactions important for that specific condition. For instance, the real reason why someone will have high blood pressure (hypertension) is not fully understood yet, but several of the chemical reactions inside the body that have relevance to make someone having high blood pressure are. So, many medicines have been developed and are available in the drugstores that work on those reactions, reducing the blood pressure.
A similar kind of situation is happening with achondroplasia. While the development of a drug directly active against FGFR3 is still in the pre-clinical phase (there are a couple of good candidates in the lab), there is at least one of those alternative options that is entering the clinical phase of its development. The phase one clinical trial of the C-type natriuretic peptide (CNP) analogue BMN-111 has just been completed, according to clinicaltrials.gov. CNP does not directly interfere with FGFR3 but works counteracting part of its effects, partially restoring bone growth, according to the animal studies already performed.
The many agents within the growth plate
CNP is one of those many factors I mentioned in the beginning of this article, having a stimulatory effect on bone growth. When you study the intricate chemical mechanisms governing the growth plate development, you learn about other agents that could be explored as an option to tackle the bone growth arrest seen in achondroplasia. One which is gaining relevance in the recent years is the protein called parathyroid hormone related protein (or peptide for some authors, PTHrP).
PTHrP is a protein closely related to PTH, the hormone which has crucial role in bone health, regulating calcium and phosphorus metabolism, and osteoblasts’ (the bone cell that builds bone) and osteoclasts’ (the bone cell that absorbs bone) activities. The lack of PTH leads to poor bone health and disturbances of blood calcium and phosphorus, causing important clinical complications. The homology (similarity) between PTH and PTHrP is great. They share quite the same structure at the so called C-terminal extremity. Before continuing, it is good to know that when you see an amino acid chain of a protein, in one extremity you will necessarily find an acid structure (the C-terminal part) and in the other you will find an amino structure (the N-terminal part). This is very important to know as each of these structures will give distinct functions to the protein.
Most importantly, in the bone both PTH and PTHrP exert their functions (or signal) through coupling with the same cell membrane receptor, called PTH receptor 1 (PTHR1), so it is logical to expect that the reactions caused by PTH and PTHrP would be very similar. You might remember that when we speak about cell membrane receptors we can think about a kind of antenna receiving (chemical) signals from outside the cell and transmitting them to the cell nucleus, where the cell response will be generated accordingly.
There are also some relevant differences between PTH and PTHrP. While PTH is produced by the parathyroid glands and circulate in the blood stream, PTHrP is found in many tissues of the body, but the exact functions in these sites are not fully understood and its relevance after birth is still on scrutiny (McCauley and Martin, 2012). As far as we know, the most relevant place where PTHrP exerts its function is exactly the growth plate cartilage.
PTHrP in the cartilage growth plate
The main effect of PTHrP in the growth plate is to keep chondrocytes in a proliferation state (in other words, keep them multiplying). Having in mind that both PTH and PTHrP use the same receptor, it makes sense to think that PTH could act in the same way PTHrP does in the chondrocyte. 

To increase the complexity, PTHrP acts in concert with another very important growth modulator called Indian HedgeHog (IHH, I know, I know, scientists are very creative naming organic molecules). IHH is fundamental for the growth plate development and one of its actions is to stimulate cells in the perichondrium (the structure that surrounds the chondrocytes and the matrix) and those chondrocytes laying in the resting zone to release PTHrP, which in turn, when binding to PTHR1, induces chondrocytes to proliferate and prevents them to start the maturation process. When the stimulated chondrocytes get far away from the PTHrP releasing site they start to mature (hypertrophy) and enter in the next phase of their life cycle. There is an excellent review by Dr. Henry Kronemberg, where he describes the bone growth development and PTHrP and IHH functions in the growth plate cartilage (Nature, 2003).
Is FGFR3 reducing PTHrP production ?
As we have seen before, FGFR3 reduces the pace of chondrocyte proliferation and maturation. FGFR3 does this by overactivating two main signaling cascades within the chondrocyte, the MAPK and STAT1 pathways (reviewed here). Now, think about this: IHH is a protein produced by hypertrophic (mature) chondrocytes, those cells in the end of the growth cycle within the cartilage. It is reasonable to think that FGFR3, by reducing the number of chondrocytes reaching hypertrophy, could be reducing the amount of IHH production. This in turn could lead to a reduction of PTHrP, which we already know that stimulate chondrocytes to proliferate. So, it is also reasonable to think that part of FGFR3 actions in the control of bone growth is indirect, by reducing the availability of PTHrP. In fact, there is already evidence of this effect (Chen L et al., 2001).
In this article, we have briefly reviewed some properties of PTH and the closely related PTHrP. In the next article we will start to explore the potential use of PTH or PTHrP to treat achondroplasia.

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