Sunday, October 6, 2019

Treating achondroplasia: unveiling the mechanism of action of statins on bone growth


The text below could look very technical, but you can read more about the basics in other articles of this blog. You just need to go to the index page in your preferred language (English, Spanish or Portuguese; see the bar on top of this page) to find out more information about everything discussed here, such as the growth plate and statins. I have also added several links to those articles throughout the text. 

What's the role of FGFR3 in bone growth?

Bone growth is a tightly controlled process that takes place within thin layers of cartilage located in the extremities of children's long bones, the growth plates. The cells responsible for the bone growth in the growth plates are called chondrocytes (Figure 1) (1).

Figure 1. Cartilage growth plate structure.

As we know, fibroblast growth factor receptor 3 (FGFR3) helps modulating the chondrocyte cell cycle within the growth plate through two main chemical pathways, one managed by a group of enzymes called MAPK and the other defined by its main enzyme STAT1. While STAT1 controls the cell's multiplication (proliferation) pace, the MAPK pathway is a key controller of the chondrocyte differentiation (hypertrophy) pace (Figure 2) (1). FGFR3, working through these pathways, inhibits bone growth.

Figure 2. FGFR3 pathways.

Signaling pathways activated by FGF/FGFR. FGFs induce dimerization, kinase activation and transphosphorylation of tyrosine residues of FGFRs, leading to activation of downstream signaling pathways. Multiple pathways are stimulated by FGF/FGFR signaling such as Ras-MAP kinase, PI-3 kinase/AKT and PLC-γ pathways. Furthermore, FGF signaling can also stimulate STAT1/p21 pathway. FGF/FGFR signaling also phosphorylates the Shc and Src protein. FGF/FGFR play crucial roles in the regulation of proliferation, differentiation and apoptosis of chondrocytes via downstream signaling pathways. From Su N et al., Bone Res. 2014 (2). Reproduced here for educational purposes only.

Don't worry about the complexity here, visit the blog's glossary for a brief description of the growth plate and its layers. Other articles of the blog also contain more detailed descriptions of the growth plate (you could try this one).

Statins for achondroplasia?

Statins have been under the spotlight since 2014, when a Japanese group published an elegant study exploring the use of statins for achondroplasia: they found out that statins were able to rescue bone growth in a model of achondroplasia (you can read more here) (3). However, they could not elucidate how those drugs were working (their mechanism of action). Later on, the Czech group lead by Dr. Pavel Krejci published a study in which they ruled out any direct effect of statins on FGFR3 (4), keeping the question of how statins could have rescued bone growth in that original study without an appropriate answer. 

Thinking about therapeutic solutions for achondroplasia statins could turn to be a handy solution: they are inexpensive, have a known safety profile and have been largely used for several clinical indications, including in children and pregnant women. Read more about statins here. 

If statins don't block FGFR3, how do they rescue bone growth?

  • Statins restore chondrocyte proliferation
A very recent study published by another Japanese group seems to have finally unveiled the mechanism of action of these drugs, explaining how statins could induce bone growth in achondroplasia.

Ishikawa et al. (5) found out that fluvastatin, one of the statins, was able to increase the expression of one of the key regulators of bone growth, a protein called Indian Hedgehog (IHH). IHH, in turn, induces the release of a local growth plate peptide called Peptide related to Parathyroid Hormone (PTHrP). When PTHrP is released in the growth plate, it stimulates chondrocytes to stay in a proliferative state (1), delaying their transition to the hypertrophic state. This article of the blog has more information about the IHH-PTHrP activities in the growth plate.

Therefore, both IHH and PTHrP are bone growth promoters, in contrast with FGFR3, which works naturally as a growth brake in the growth plate.

Is there any correlation between FGFR3 and IHH ? 

Back in 2001, Chen et al. (6) demonstrated that FGFR3 had a direct inhibitory effect in the IHH-PTHrP axis in the growth plate (Figure 3). The exact mechanism by which FGFR3 inhibits IHH and PTHrP remains elusive although it seems that one of the chemical pathways activated through FGFR3 (the STAT1 pathway - Figure 2) induces cell cycle inhibitors (agents that block cell multiplication) leading to inhibition of IHH (which is, as said above, a cell proliferation promoter).

Figure 3. Crosstalk between FGFR3 and IHH in the growth plate.

Model of the relations between FGF-FGFR3 and IHH-PTHrP–PTHrP-R signaling in endochondral bone formation. FGF-FGFR3 and IHH-PTHrP–PTHrP-R signals are transmitted by two integrated parallel pathways that mediate both overlapping and distinct functions during the growth of long bones. Both FGFR3 and IHH affect chondrocyte proliferation. However, FGFR3 is a negative regulator of bone growth, whereas IHH positively regulates bone growth. Evidence suggests that FGF-FGFR3 signaling induces activation of STAT proteins, upregulation of the expression of cell cycle inhibitors and downregulation of IHH expression. Both FGF-FGFR3 and PTHrP–PTHrP-R signals inhibit chondrocyte differentiation, and both signals appear to act in a dominant and independent manner. From Chen L et al. Hum Mol Gen 2001;10(5):457-65 (6). Reproduced here for educational purposes only.

So, in summary Ishikawa et al. found out that statins seem to restore the IHH-PTHrP axis in chondrocytes affected by FGFR3 signaling, improving these cells' ability to proliferate.

Why is this finding important?
As we saw above, FGFR3 inhibits bone growth by reducing both the chondrocyte proliferation rate and its ability to differentiate and enlarge (to become mature, a process called hypertrophy). These two chondrocyte's stages represent the core of the bone growth process.

To put this information in context and help readers to understand its relevance it is important to know that the current most advanced potential therapy for achondroplasia, vosoritide, which is a C-type natriuretic peptide (CNP) analogue, works specifically over the MAPK pathway, so it rescues only one of the key processes regulated by FGFR3 (7).

In this context, it is possible that strategies that aim to inhibit the activity of FGFR3 directly might provide better outcomes in terms of bone growth rescue because they would be affecting both main pathways triggered by this receptor (Figure 2). This is the case of recifercept (TA-46) and infigratinib (BGJ-398) (check out the articles in the blog reviewing these molecules).

In conclusion, the data provided by Ishikawa et al. may provide grounds for investigators to explore the combination of therapies targeting the MAPK pathway - all CNP-based therapies, anti-MAPK kinase inhibitors and meclizine - with statins, taking advantage of their unique mechanisms of action. These combinations might work in sinergy to rescue bone growth in achondroplasia and in other skeletal dysplasias in which FGFR3's excessive activity plays a relevant role.


1. Long F, Ornitz DM. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 2013;5(1):a008334. Free access.

2. Su N et al. Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res. 2014;2:14003. Free access.

3. Yamashita A et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014 ;513(7519):507-11.

4. Fafilek B et al. Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage. 2017 Sep;25(9):1522-1530. Free access.

5. Ishikawa M et al. The effects of fluvastatin on indian hedgehog pathway in endochondral ossification. Cartilage. 2019 Jul 22:1947603519862318.

6. Chen L et al. A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 2001; 10(5):457-65. Free access.

7. Lorget F et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012 ;91(6):1108-14. Free access.

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