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Further confirmation of rapalogs as potential therapy for heterotopic ossification

Submitter: Benjamin Levi | blevi@med.umich.edu

Authors: Shailesh Agarwal, Yuji Mishina, and Benjamin Levi

University of Michigan

Published August 28, 2017

Fibrodysplasia ossificans progressiva (FOP) is a genetic condition caused by a hyperactivating mutation in the type I bone morphogenetic protein (BMP) receptor ACVR1 (ACVR1 R206H).  Recently, Hatsell et al have shown that, in addition to BMP, Activin A serves as a ligand for ACVR1 R206H.  We are pleased to see that Hino et al¹  have further confirmed a relationship among Activin A, BMP receptor activity, and the mTOR axis in their recent manuscript.

In two recent publicationss, we have shown that mTOR signaling is up-regulated by increased BMP receptor activity.^2,3 Using a FOP mouse model of constitutive type I BMP receptor activity (ACVR1 Q207D) and a separate traumatic HO model, we showed that rapamycin eliminates heterotopic ossification.³  Earlier this year at the annual International FOP Association (IFOPA) meeting, we subsequently showed our findings that rapamycin eliminates heterotopic ossification in the mouse model of FOP (Acvr1 R206H) generated and shared by our colleagues, Economides et al, at Regeneron.⁴ It should be noted that exploration of rapamycin as a therapeutic option in (mouse) HO (both in an FOP setting as well as trauma induced HO) was precipitated by the observation that inflammation is a shared prerequisite in these HO settings, and hence hypothesized that immune-suppressing agents such as rapamycin would be able to stop the initiation HO if administered prophylactically.  Moreover, our work did not utilize either modeling of HO in vitro or the screening of libraries of compounds – rather it was based on observations made in patients and corresponding animal models.

In their recent study, Hino et al¹ use induced pluripotent stem cells derived from FOP patients to study mTOR signaling in the setting of the FOP mutation.  Using in vitro studies, they showed that “mTOR inhibitors suppress the chondrogenic induction of FOP-iMSCs triggered by Activin A” (Fig 3). We have previously shown that mTOR inhibitors may reduce chondrogenesis through their downstream effect on hypoxia-inducible factor-1a (Hif-1a)³; previous studies have shown that Hif-1a is critical for normal embryologic chondrogenesis.⁵ Moreover, by showing that “Rapamycin suppresses Activin-A-triggered HO in FOP-ACVR1 conditional transgenic mice,” (Fig 4) Hino et al confirm our findings presented at IFOPA and add to the impetus to study rapamycin for patients with FOP.  However, further studies are clearly required to understand the mechanism by which mTOR inhibition reduces chondrogenesis. For example, it is unclear how increased BMP receptor activity leads to increased mTOR signaling. It is also unclear still whether these findings are unique to Activin A, or whether mTOR inhibition has a similar effect with any BMP receptor ligand.  Answers to these questions may allow us to generate additional targeted drugs, and may even allow us to address diseases which are not caused by genetic mutations such as trauma-induced heterotopic ossification or heterotopic ossification caused by BMP implants used for bony healing in patients.

The findings presented by Hino et al are important to everyone studying FOP.  We are excited to hear that these findings are being used to begin a clinical trial in Japan, which will hopefully have similar findings and be able to offer a therapeutic strategy for individuals with FOP. We will continue to follow these advances closely and commend the research group for their efforts and findings.  Rapamycin is a generally well-tolerated drug used for pediatric and adult conditions. Therefore, we believe that rapamycin, or other mTOR inhibitors/rapalogs, hold great promise in treating this painful disease process while minimizing treatment-associated morbidity.

 

*Acknowledgements: BL laboratory collaborates with Boehringer Ingleheim on a project not presented here. BL laboratory holds a patent for HIF1 inhibition including rapalogs for prevention of heterotopic ossification which is not yet licensed.

 

REFERENCES

1.         Hino, K., et al. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. The Journal of clinical investigation (2017).

2.         Agarwal, S., et al. mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration. JCI Insight 1, e89805 (2016).

3.         Agarwal, S., et al. Inhibition of Hif1alpha prevents both trauma-induced and genetic heterotopic ossification. Proceedings of the National Academy of Sciences of the United States of America 113, E338-347 (2016).

4.         Hatsell, S.J., et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Science translational medicine 7, 303ra137 (2015).

5.         Provot, S., et al. Hif-1alpha regulates differentiation of limb bud mesenchyme and joint development. The Journal of cell biology 177, 451-464 (2007).