Fibrodysplasia Ossificans Progressiva: bone formation outside the skeleton

By Sonja van Scheijen

Figure 1: a 3D-reconstructed image CT-scan of a 12-year old patient with FOP (3)

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, genetic disorder where, slowly, but progressively extra bone formation develops outside the body’s skeleton. A flare-up of new bone formation can be triggered spontaneously or by everyday traumas to the body, such as from falling or bumping against the kitchen counter. This bone formation, which can limit mobility and can be incredibly painful during flare-ups, is a process called heterotopic ossification (HO) (Figure 1). Surgically removing the aberrant bone or even taking a biopsy is not a good idea, because this in itself induces new trauma and thus new HO (1). For this reason, research and treatment of FOP is challenging. Nonetheless, researchers and doctors all over the world are trying to find treatments for the (estimated worldwide) 4000 FOP patients. The Amsterdam UMC Location VUmc FOP research centre is a leading example of this. Researchers and clinicians with a range of backgrounds including genetics, dentistry and medicine are working with patients to investigate the disease further.

From misdiagnosis to loss of mobility

Figure 2: malformations of the big toes of a child with FOP (1)

A malformation of  the big toes is usually the only indication of FOP at birth (Figure 2) (2). During childhood, the first signs of heterotopic ossification are usually present along the head, neck and/or back with pain, irritation and soft tissue swelling. Since children appear otherwise healthy, not all of them are correctly diagnosed with FOP at first. After the first stage of soft tissue swelling, there is a decrease in swelling as the maturation stage of HO starts and ossification occurs. If this happens around a joint, this can lead to reduced mobility (1). Approximately half of interviewed FOP-patients indicated a permanent loss of mobility due to procedures conducted because of misdiagnoses (4). Most patients use wheelchairs by the end of their 20s and the average lifespan is 40 years (5). The symptom severity and frequency of flare-ups vary greatly between patients, however the ossification leads in all cases to accumulating immobilization.

A village of molecules and proteins

The aberrant bone formation is caused by a single point mutation in the acvr1 gene, a receptor involved in bone formation. It takes a village to raise a child, similarly, it also takes a village of molecules and proteins to develop and regulate bone formation. Usually these village occupants are tightly regulated to ensure bone formation at the right time at the right place. In times of bone growth (during a child’s growth spurt or to repair a broken bone) the growth factor Bone Morphogenetic Protein (BMP) occupies the receptor to stimulate bone formation. In times where bone growth should not take place (the majority of the time), another factor, Activin A, takes its place on the receptor to inhibit bone growth. Together, BMP and Activin A switch the receptor on and off to regulate the bone formation. To prevent the receptor from acting on its own, a different factor binds the receptor on the inside of the cell (6) (Figure 3, left-side). 

Figure 3: An overview of the relevant pathway in FOP. Left the non-FOP pathway is shown. FKBP1A prevents leaky activation, BMP activates the ACVR1 receptor and Activin A inhibits the receptor. Activation of the receptor leads to the induction of genes that lead to bone formation. On the right the same pathway is shown for FOP: FKBP1A cannot bind anymore, the receptor is activated without BMP and Activin A acts as an activator, hereby leading to enhanced bone formation (Created with BioRender.com).

This point mutation of the acvr gene causes unwanted bone growth in three ways(3). Firstly, the receptor does not need the growth factor to be active, leading to increased bone formation. Secondly, the factor Activin A stimulates bone growth instead of inhibiting it. Thirdly, the factor stationed on the inside of the cell no longer prevents the receptor from acting on its own (7) (Figure 3, right-side). Therefore, one single point mutation can disrupt a whole village of molecules and proteins to alter their function.

Will the LUMINA-1 trial improve outcomes for FOP patients?

There are a number of multi-site clinical trials underway in the hope of finding a drug that alleviates the symptoms of FOP. The LUMINA-1 trial at Amsterdam UMC is an example, which uses an antibody that binds and sequesters Activin A. In previous animal studies, the LUMINA-1 antibody managed to prevent further aberrant bone formation (8) and results from the phase 1 trials indicated that the drug had no dangerous side-effects in healthy participants (9). The pharmaceutical company that produces the antibody, announced very promising results early in the phase 2 trial: patients receiving the antibody showed a 90% reduction compared to placebo of new HO occurrences (10). However, in late 2020, the trials were halted. It is currently under further investigation whether some patient deaths were caused by the trial’s antibody treatment (11).

Where to next?

Many riddles still need to be solved for understanding FOP, such as why symptom severity can vary so greatly among patients. These answers might even be unlocked in bone signalling pathways downstream of the ACVR receptor. The most effective treatment here may finally involve a combination of approaches, such as inhibiting Activin A together with a BMP receptor inhibitor. Either way, it will take a village of researchers, doctors and patients to further understand and find a treatment for FOP.

Want to learn more?

FOP stichting (Dutch foundation): https://fopstichting.nl/ 

International Fibrodysplasia Ossificans Progressiva Association: https://www.ifopa.org/ (also take a look at their YouTube channel)

About the writer

Sonja is studying both the Biomolecular Sciences and the Philosophy, Bioethics, and Health master degree at VU. She enjoys doing many things at the same time: her interests range from the influence of literature on society (and vice versa) to the molecular basis of rare genetic diseases. She has written her literature thesis on the role of osteoclasts (“bone eating cells”) in heterotopic ossification and has a special interest in FOP.

This article was revised on 12 March 2021 to refine editorial tone about patient experience.

Special thanks to Esmée Botman for scientific contribution to this article.

The banner was made especially for this article by Sara Said. Want to see more of her work? Visit her Instagram: sarasaidart.

Further reading

  1. Pignolo, R. J., Shore, E. M., & Kaplan, F. S. (2011). Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet journal of rare diseases, 6(1), 1-6.

  2. Towler, O. W., Peck, S. H., Kaplan, F. S., & Shore, E. M. (2020). Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Developmental Biology, 470, 136-146.

  3. Shore, E. M., Xu, M., Feldman, G. J., Fenstermacher, D. A., Cho, T. J., Choi, I. H., … & Morhart, R. (2006). A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature genetics, 38(5), 525-527.

  4. Kitterman, J. A., Kantanie, S., Rocke, D. M., & Kaplan, F. S. (2005). Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics, 116(5), e654-e661.

  5. Kaplan, F. S., Zasloff, M. A., Kitterman, J. A., Shore, E. M., Hong, C. C., & Rocke, D. M. (2010). Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. The Journal of Bone and Joint Surgery. American volume., 92(3), 686.

  6. Valer, J. A., Sánchez-de-Diego, C., Pimenta-Lopes, C., Rosa, J. L., & Ventura, F. (2019). ACVR1 Function in Health and Disease. Cells, 8(11), 1366.

  7. Wolken, D. M. A., Idone, V., Hatsell, S. J., Paul, B. Y., & Economides, A. N. (2018). The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva. Bone, 109, 210–217.

  8. Hatsell, S. J., Idone, V., Wolken, D. M. A., Huang, L., Kim, H. J., Wang, L., … & Das, N. (2015). ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Science translational medicine, 7(303), 303ra137-303ra137

  9. Vanhoutte, F., Liang, S., Ruddy, M., Zhao, A., Drewery, T., Wang, Y., … & Davis, J. D. (2020). Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti‐Activin A): Results From a First‐in‐Human Phase 1 Study. The Journal of Clinical Pharmacology, 60(11), 1424-1431. 

  10. Regeneron Pharmaceuticals, Inc. (2020, January 9). Regeneron Announces Encouraging Garetosmab Phase 2 Results in Patients with Ultra-Rare Debilitating Bone Disease. Retrieved 28 February 2021, from https://www.prnewswire.com/news-releases/regeneron-announces-encouraging-garetosmab-phase-2-results-in-patients-with-ultra-rare-debilitating-bone-disease-300984302.html