Why do chondrocytes stop in achondroplasia? part 2

Introduction

In the last regular article we have reviewed an interesting hypothesis formulated by Dr. Pavel Krejci, one of the most enthusiastic investigators of the fibroblast growth factor receptor 3 (FGFR3) molecular properties, to explain why FGFR3, a known growth stimulator for most of the cells of the body, works in the opposite direction in chondrocytes. (1)

In brief, FGFR3 is a natural brake for chondrocyte growth, helping this cell, the master of bone growth, to regulate their own proliferation (multiplication) pace. The G380R mutation in FGFR3, the cause of achondroplasia (2), makes this enzyme more active than normal, thus forcing the chondrocytes to just stop multiplying and maturing, making the bone to stop growing. The usual action of FGFR3 in chondrocytes is important for normal bone growth: if there was no FGFR3, then bones would grow excessively and bad consequences would also arise. (3,4)

We also saw that FGFR3 works through a number of what we call signaling cascades to exert its effects in chondrocytes and one of these cascades, the mitogen activated protein kinase (MAPK) pathway seems to be of key relevance in bone growth (figure 1;[5]). The MAPK cascade is a key positive driver of cell proliferation, growth, specialization and survival in most cells of the body, including cancer cells. (6) 



Figure 1. FGFR3 - MAPK (ERK) signaling pathway

As we saw in the last article, in normal conditions, the cell has quality control mechanisms that are activated when something seems to be going wrong with its functions, for example, when it receives too much growth stimuli. This makes the cell to "interpret" the excessive stimuli as dangerous and to turn on the control system. (7)

On the contrary, in cancer those controls are lost and cells multiply freely. In some types of cancer, cancer cells start to produce FGFR3 bearing the same mutation which, when occurring spontaneously, causes a more severe and lethal kind of chondrodysplasia, called tanatophoric dysplasia (TD). In TD, FGFR3 is so active that it doesn't need to be turned on by a FGF, it is always active and works alone (what is called constitutive activation).(8) This makes the FGFR3-MAPK pathway extremely active and the cancer cell is driven to multiply without control.

MAPK in chondrocytes 

Chondrocytes seem to be an exception in the rule of MAPK: instead of growing under FGFR3-MAPK influence, they reduce their growth pace and, according to Dr. Krejci, this would be the result of chondrocytes using the quality control system to react to the stimulus given by FGFR3-MAPK. (1,9) The cells using this control system would be entering in what is called a state of cell senescence: they would keep some cell functions but would be unable to multiply (no chondrocyte multiplying = no bone growth). As we mentioned in the previous article, this concept could be questioned: the mutation makes chondrocytes going to senescence, but isn't the normal function of FGFR3 to reduce chondrocyte growth pace? Is the senescence phenomenon being activated in chondrocytes even under normal FGFR3 activation?

I have been thinking in this problem lately and couldn't find a right answer for these questions. Cell senescence is often mediated by a famous control protein called p53. It has a couple of other companions and they are considered the mainstream of this kind of proliferation control. (7) Furthermore, it has been already found that chondrocytes under the influence of MAPK also trigger another control protein called p107. (10)  And finally, it has also been shown that members of the Sprouty family of proteins regulate FGFRs and other cell enzymes and can also trigger senescence. (11) However, it is difficult to say why in normal conditions (think in the normal FGFR3) this control would be turned on in chondrocytes and would be enhanced in cells bearing the mutated receptor. How could this happen?

We already know that FGFR3 is only one of many other players controlling the rhythm of bone growth, most of them acting as positive modulators, including parathyroid hormone and its related peptide (PTH, PTHrP), C-type natriuretic peptide (CNP), growth hormone/insulin growth factor 1 (GH, IGF1) among others.

Perhaps, the sum of all these positive stimuli, added by the extra stimulus given by FGFR3 (remember that FGFR3 is a positive growth stimulator for other cells) is the trigger of these growth control systems in chondrocytes. The question is, either run by p53, p107 or Sprouty proteins these systems are the same in all cells, so why would chondrocytes behave differently?

Well, this would need to be demonstrated.

A final note

In the last article I said that the next one would be about targeting the MAPK pathway to treat achondroplasia. This is the third article or note I published here since then. The topic about chondrocyte senescence is very important and I couldn't help thinking more about it. In the next article, we will be finally reviewing more closely the use of MAPK inhibitors that are being explored in the treatment of cancer to treat achondroplasia.

References

1. Krejci P. The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate. Mutat Res Rev Mutat Res 2014;759:40-8.

2. Bellus GA et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 1995;56(2):368-73. Free access.

3. Colvin J et al. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genetics 1996; 12:390-7.

4. Toydemir RM et al. Novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) Syndrome. Am J Hum Genet 2006;79(5):935-41. Free access.

5. Foldynova-Trantirkova S et al. Sixteen years and counting: the current understanding of 
fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat 2012; 33:29–41. Free access.

6. Santarpia L et al. Targeting the Mitogen-activated protein kinase RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets 2012; 16(1): 103–19. Free access.

7. Campisi J & Fagagna FA. Cellular senescence: when bad things happen to good cells. Nature Rev Mol Cell Biol 2007;8:729-40.

8. d'Avis PY et al. Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I. Cell Growth Differ 1998;9(1):71-8. Free access.

9. Krejci et al. FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence. Bone 2010; 47:102–10. Free access under certain conditions.

10. Kolupaeva V et al.The B55α regulatory subunit of protein phosphatase 2A mediates fibroblast growth factor-induced p107 dephosphorylation and growth arrest in chondrocytes. Mol Cell Biol 2013;33(15):2865-78.

11. Macià A et al. Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis. Cell Death Differ 2014; 21(2):333-43.