Source of Out-of-Control Bone Growth Discovered

“We always knew that heterotopic, or misplaced, bone growth was supplied by a rich [blood] vasculature, but we never suspected that cells from the blood vessels, when triggered by cells from the immune system, could undergo a metamorphosis that becomes a second skeleton,” said senior author Frederick S. Kaplan, Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine. “When these components interact pathologically, as in the rare disease FOP, devastating results occur. We want to fix that.”
   
FOP stands for fibrodysplasia ossificans progressiva, a rare condition afflicting only 700 known individuals in which muscle tissue changes into bone, forming a second skeleton. Understanding the out-of-control muscle-to-bone process could lead to understanding similar disorders that occur following injuries to the head, joints and spinal cord.
   
The study used mice that had been genetically engineered so the scientists could follow specific labeled cell lines through the abnormal bone formation process. In 2006, the same Penn team found that FOP is triggered by a mutant gene that turns on a “switch” for producing skeleton-stimulating biochemicals known as bone morphogenetic proteins (BMPs). The next year, they discovered that inflammation plays a key role in activating the bone-forming process.
   
The current study has shown that immune-system cells that respond to an injury and its associated inflammation appear to interact with cells that line the interior of blood vessels, touching off an aberrant transformation of muscle to bone when the BMP gene is damaged or overactive. But the researchers found that blood vessel cells account for only half of the cells that make the process happen, indicating that there are other pools of cells waiting to be identified.
   
“BMPs regulate a great number of essential physiological processes,” said co-corresponding author David J. Goldhamer, associate professor at the Center for Regenerative Biology at the University of Connecticut. “For this reason, development of therapies for misplaced bone growth that specifically target offending progenitor cell populations is of primary importance in order to minimize collateral effects. Identification of progenitor cells directly involved in heterotopic bone formation is a critical first step toward this goal.”