Mechanism of Action and Affected Systems
Much of what we know about FOP in humans comes from autopsies.1 Though heterotopic ossification is the hallmark symptom of this disease, other organ systems can be significantly disrupted. This may include spinal ligament ossification, thoracic insufficiency syndrome, and clear CNS deformities. Often, the full extent of the disease’s effects cannot be observed until after death.
The macroscopic damage that can occur as a result of FOP is visible to the naked eye, but a thorough understanding of the disease pathology at the biochemical level will be critical for treatment. FOP is the result of a mutation in the ACVR1 gene. While the disease itself is autosomal dominant and only one copy of the defective gene is needed for dysregulation to occur, those who are homozygous for the disease exhibit stronger symptoms. The ACVR1 gene codes for the activin A receptor type 1. This receptor plays an essential role in bone morphogenic protein (BMP) signaling.2
BMP signaling itself is pivotal in the architecture of the body as it develops. As tissues differentiate, this morphogenic protein initiates chondrogenic differentiation and subsequent ossification of cartilage. This will end up forming the skeleton of the body. The ACVR1 gene normally ceases to function following skeleton formation in the womb. Once the body is developed, there’s no need to further ossify cartilage to generate a skeleton. The process is largely unused in adult organisms.3
Following injury, the body begins the inflammation response. Chemical signaling molecules leak out into the surrounding tissue, releasing histamine and prostaglandin among others. The affected area begins to swell as fluid leaks into it. Lymphocytes from this fluid begin to flood the affected area. These lymphocytes have a significant amount of bone morphogenic protein 4 (BMP4), a specific type of BMP that is very evolutionarily conserved and only capable of binding to ACVR1 during embryonic development.2
ACVR1R206H is a gain-of-function mutation that confers a significantly different ligand response. The receptor, when mutated, is able to bind BMP as a ligand. This ligand binding causes chondrogenic differentiation and leads to the heterotopic ossification that ossifies cartilage into bone. This begins to wreak havoc on the body, allowing the ACVR1 receptors to, when given ample ligand, cause bone formation. As damage accumulates over a lifetime, patients can suffer from an alarming decrease in mobility, respiratory issues,
circulatory issues, and joint fusion that locks limbs in place.4
The increased ligand binding capability of ACVR1R206H also implies that, in the normally functioning receptor, there is some type of inhibitory mechanism that prevents the binding of these ligands to the proteins, and by altering the structure through this point mutation the inhibitory ligand cannot bind, leaving the receptor susceptible to binding by BMP. Restoration of the inhibitory ligand binding, or the synthesis of a new ligand to inhibit this receptor, both appear to be worthwhile approaches to treating this dysregulation.
Activin A, an important molecular signaling molecule, cannot act as a ligand for the ACVR1 receptor under normal physiological conditions. Activin A instead interacts with the ACVR1B receptor and the ACVR1C receptor to initiate signaling. ACVR1206H (The most common FOP variant), however, has conferred a gain-of-function mutation that allows it to be activated by Activin A. In FOP, Activin A acts similarly to BMP and binds to the ACVR1206H receptor, causing phosphorylation of SMAD1/5/8.2,3,4 In essence, Activin A is able to product the same response that BMP would product, creating a situation in which the ACVR1 receptor is constitutively active. BMP itself retains the ability to also bind to the receptor, resulting in a situation in which both signaling molecules are activating the receptor. Overamplification of the signal, especially during inflammation when BMP floods to the site, is what causes the signal cascade that culminates in heterotopic ossification. This has proven to be critical in the heterotopic ossification of FOP. Activin A has been labeled as an obligate molecule, meaning that it is essential for the symptoms of FOP to occur. The potential of Activin A as a drug target is grand, though it has yet to be realized.
Hypoxia is also though to play a role in heterotopic ossification due to FOP.5 During the inflammatory response, the inflamed environment can become hypoxic. During the formation of an injury-induced FOP lesion, the site of injury is markedly hypoxic. This hypotoxicity comes with increased levels of the HIF heterodimeric dimer, made of HIF-α and HIF-β. HIF-β is present at all times, but HIF-α is made oxygen-sensitive through ubiquitinoylation due to oxygen-dependent prolyl-hydroxylation.5 A lack of oxygen inhibits this prolyl-hydroxylation, allowing THF-α to evade ubiquitinoylation, dimerize with THF-β, and product the cell’s hypoxia response.5
The prevention of degradation of HIF-α occurs during both inflammation and hypoxia. Recently, it was discovered that this hypoxia signaling pathway and the signaling pathway of FOP are intricately linked. By preventing the stabilization of HIF-α in a mouse model, researchers have been able to successfully inhibit the BMP-mediated heterotopic ossification in FOP. HIF-α, like activin A, appears to be yet another crucial molecule in FOP. To researchers, this connection marks yet another potential drug target to treat this disorder.
- Tian, Shengjie, Jianhua Zhu, and Yaogang Lu. “Difficult Diagnosis and Genetic Analysis of Fibrodysplasia Ossificans Progressiva: A Case Report.” BMC Medical Genetics 19, no. 1 (February 27, 2018): 30. https://doi.org/10.1186/s12881-018-0543-7.
- Lees-Shepard, John B., Masakazu Yamamoto, Arpita A. Biswas, Sean J. Stoessel, Sarah-Anne E. Nicholas, Cathy A. Cogswell, Parvathi M. Devarakonda, et al. “Activin-Dependent Signaling in Fibro/Adipogenic Progenitors Causes Fibrodysplasia Ossificans Progressiva.” Nature Communications 9, no. 1 (February 2, 2018): 471. https://doi.org/10.1038/s41467-018-02872-2.
- Hildebrand, Laura, Katja Stange, Alexandra Deichsel, Manfred Gossen, and Petra Seemann. “The Fibrodysplasia Ossificans Progressiva (FOP) Mutation p.R206H in ACVR1 Confers an Altered Ligand Response.” Cellular Signalling 29 (2017): 23–30. https://doi.org/10.1016/j.cellsig.2016.10.001.
- Upadhyay, Jaymin, LiQin Xie, Lily Huang, Nanditha Das, Rachel C. Stewart, Morgan C. Lyon, Keryn Palmer, et al. “The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent.” Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research 32, no. 12 (December 2017): 2489–99. https://doi.org/10.1002/jbmr.3235.
- Wang, Haitao, Carter Lindborg, Vitali Lounev, Jung-Hoon Kim, Ruth McCarrick-Walmsley, Meiqi Xu, Laura Mangiavini, et al. “Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling.” Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research 31, no. 9 (September 2016): 1652–65. https://doi.org/10.1002/jbmr.2848.