Condemned to a Skeletal Prison

Feb 28 2013 Published by under Science

*Re-blogged from Amasian Science for Rare Disease Day.

Imagine going to sleep and waking up the next morning not able to bend your elbow or knee. Or imagine having difficulty drawing breath because your rib cage is starting to fuse. Imagine being unable to enjoy your favorite cut of steak because your jaw has locked into place. Even worse, imagine having a limb amputated because you've been misdiagnosed with cancer. This is the harsh reality facing patients with fibrodysplasia ossificans progressiva (FOP), a rare, genetic disease affecting 1 in 2 million people (700 known cases worldwide, 185 in the US), where soft tissues--like muscle and connective tissue--are progressively replaced by bone. Often beginning in the neck, ribbons of bone spread through the shoulders, along the back, trunk, and limbs of the body eventually freezing patients in a skeletal cage.

Curiously, FOP patients are born by and large symptom free, the only consistent tell-tale sign being malformed great toes:

Extraskeletal bone formation occurs sometime in the first two decades of life, usually during childhood. Bone formation is preceded by a painful, inflammatory flareup, the cause of which is unknown. A particularly insidious feature of the disease is that trauma or injury can induce these flareups, meaning that undergoing surgery to remove the extra bone only exacerbates the problem. Bumps and bruises we typically overlook cause alarm for FOP patients. Even injections, such as vaccinations, are a source of concern. Currently, while there is no cure, treatment revolves around reducing inflammation and controlling pain using corticosteriods, NSAIDS, or COX-2 inhibitors such as Vioxx (before it was pulled from the market).

A mystery unraveled

While the earliest description of FOP dates back to the late 17th century, the cause of the disease remained an enigma for centuries until 2006, when researchers at the University of Pennsylvania linked the disease to a mutation found in FOP patients (1). The mutation affects one copy of the ACVR1(ALK2) gene, which encodes a protein important in relaying communication between cells. In the body, cells can send signals to instruct other cells to start forming bone via Bone Morphogenetic Proteins (BMP)--thus named for their ability to induce bone growth. ACVR1 is a type I receptor for BMPs and, with the help of the BMP type II receptor, acts like an antenna that receives these signals and transmits the encoded instructions to the cell.

Cellular messaging. Cells communicate with each other by sending proteins "messages" that are received by receptors on the cell surface. BMPs are just one of many types of different protein messages. These messages can instruct other cells to grow, divide, transform into other types of cells, or even self-destruct. This is analogous to people communicating by text message. BMPs and the ACVR1 receptor can be thought of as the text message and the cell phone receiving the text message, respectively.* 

Studies in zebrafish, fruit flies and mammalian cell culture all indicate that the mutant ACVR1 receptor linked to FOP has gone rogue, capable of transmitting the instructions without having to receive the initial BMP signal (2-4). The mutant receptor acts as though its power switch has been permanently flipped to the "on" position. More recently, scientists have provided even more direct evidence that the mutant form of ACVR1 is responsible for FOP. Through a trick of genetic engineering known as "gene knock-in", the researchers at UPenn were able to replace one copy of the normal ACVR1 gene in mice with the mutant form associated with FOP. The resulting mutant mice displayed many of the hallmarks of FOP: "malformed first digits in the hind limbs and post-natal extra-skeletal bone formation" that occurs both spontaneously and as a result of injury (5).

Adapted from Figure 2 (5). (A) Characteristic great toe malformation in FOP patient. (B) FOP mutant mice (right panels) displayed malformation of the first digits of the hind-limbs (circled) at birth. (C) Skeleton of FOP mouse with arrows to indicate extra-skeletal bone formation. Fusion of cervical vertebrae (C3-C5) (D), fusion of costovertebral malformations and fusion of vertebrae (asterisks) (E), and abnormal bone growth (arrows) (F) are observed in the mouse and FOP patients.

One of the limitations of their knock-in technique, however, was that the replacement of the normal ACVR1 gene with the mutant version was incomplete--it occured in most, but not all, of the cells in the mice. This produced chimeric mice, which were mosaics of cells that had one copy of the mutated ACVR1 gene ("FOP" cells) and cells that had two normal copies of the ACVR1 gene. Exploiting this mixed nature of the mice, the researchers were able to study how "FOP" cells interacted with normal cells. Surprisingly, they found that in the presence of "FOP" cells even normal cells were turning into bone. This suggests that cells that have the faulty ACVR1 receptor can also instruct normal cells to turn into bone through an unidentified mechanism.

Marching toward a cure

With these findings scientists are beginning to devise strategies and design drugs that can either specifically turn off the expression of the mutant ACVR1 gene or turn off the aberrant activity of the mutant, providing hope that a cure or, at very least, an effective treatment is on the horizon. While some of these avenues are promising, a viable treatment is far from reaching the market. To find a cure will require more research, which in turn requires money. Because FOP is such a rare disease it often flies under the radar when it comes to research funding. Currently, an estimated $1.5 million a year is spent on FOP research, 25% of which is funded by institutions like the NIH and the Orthopaedic Research and Education Foundation. Incredibly, the remaining 75% is generated through donations and FOP family fundraising. If you would like to help or find out more about FOP, please visit the International FOP Association website.

Featured Image: Harry Eastlack, a man who lived with FOP, donated his skeleton to science. His skeleton is on display at the Mütter Museum.

1. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May;38(5):525-7

2. Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest. 2009 Nov;119(11):3462-72. doi: 10.1172/JCI37412

3. Le VQ, Wharton KA. Hyperactive BMP signaling induced by ALK2(R206H) requirestype II receptor function in a Drosophila model for classic fibrodysplasiaossificans progressiva. Dev Dyn. 2012 Jan;241(1):200-14. doi: 10.1002/dvdy.22779

4. van Dinther M, Visser N, de Gorter DJ, Doorn J, Goumans MJ, de Boer J, ten Dijke P. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res. 2010 Jun;25(6):1208-15

5. Chakkalakal, S., Zhang, D., Culbert, A., Convente, M., Caron, R., Wright, A., Maidment, A., Kaplan, F., & Shore, E. (2012). An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva Journal of Bone and Mineral Research DOI: 10.1002/jbmr.1637

*7.10.12 - Updated figure. See this post.

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