AsianScientist (Dec. 8, 2015) – A protein associated with inflammation may be responsible for causing the genetic disease known as Stone Man Syndrome, scientists have found. Their research, published in Proceedings of the National Academy of Sciences, used reprogrammed cells to help them understand what was sparking bone growth in the soft tissue of those with the disease.
Fibrodysplasia ossificans progressive (FOP) is a rare, but devastating genetic disease where bone is grown within soft tissue, such as skeletal muscle. It is known as Stone Man Syndrome because the patient’s body ossifies into a statue-like state. It is a genetic disease, but patients do not show symptoms until their school-aged years.
Normally, an immune response or trauma triggers the disease. This complicates study of FOP because the trauma associated with acquiring the patient’s cells could stimulate the irregular bone growth. For the same reason, surgical treatments that remove excessive bone are not an option, because these too will only cause more bone growth in the post-operation healing period.
Induced pluripotent stem (iPS) cells offer an attractive model to study the disease, because researchers can take cells from the patient that are unaffected by FOP and then reprogram the cells into soft tissue cells for study.
Researchers at the Center for iPS Cell Research and Application (CiRA), Kyoto University, took advantage of this strategy by reprogramming FOP patient cells and then seeking candidate molecules that could explain how the disease initiates. The researchers focused on bone morphogenetic proteins (BMP). BMP are what stimulate bone healing after a fracture or break. However, in FOP patients, BMP signaling appears hyperactive.
“There are two popular theories”, explains Makoto Ikeya, an associate professor at CiRA involved in the study. “In one, BMP signaling is always active. In the other, BMP signaling is abnormally strong when activated.”
In the quest to develop drugs to treat FOP, scientists have normally focused on molecules associated with BMP signaling. However, researchers from Professor Junya Tochuchda’s lab instead looked at molecules related with inflammation. They found that Activin-A as a candidate drug target.
“Because patients normally show FOP symptoms after trauma or inflammation, we thought this would be a good strategy,” Ikeya said.
Using iPS cell technology, the scientists found that only cells harboring the FOP gene mutation would respond to Activin-A by significantly increasing their BMP signaling. Further, transplanting these cells into mice and stimulating them with Activin-A led to abnormal bone.
According to another author of the study, CiRA Professor Junya Toguchida, the discovered relationship between inflammation and bone formation gives a whole new perspective on treatments.
“Our model provides a new platform for drug discovery and the study of bone formation that did not exist before”, he said.
The article can be found at: Hino et al. (2015) Neofunction of ACVR1 in Fibrodysplasia Ossificans Progressiva.
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Source: Center for IPS Cell Research and Application.
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