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Spotlight on Research 2009
August 2009 (historical)
Bone Formation Gone Awry — NIAMS Researchers Identify Cell Involved in Pathology
Heterotopic ossification is a condition in which bone grows within soft tissue, impeding the normal function of muscles, tendons, and ligaments. Scientists have been trying for some time to isolate the type of cells that lead to this abnormal bone formation, without success. Now, researchers supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have identified a cell that contributes to this debilitating condition.
Heterotopic ossification can develop in people in response to a traumatic injury, including severe head injuries, spinal cord injuries, war injuries, and even hip replacements. It can also be a genetic disease. The most severe of the genetic diseases is a rare, inherited condition known as fibrodysplasia ossificans progressiva, or FOP, in which the body eventually forms a second skeleton from its own muscles, tendons, and ligaments. If the soft tissue of a patient with FOP becomes injured, it tries to repair itself by manufacturing bone in place of the muscle or other soft tissue. Over time, as more bone grows across an increasing number of joints, it may become impossible for the patient to reach, walk, eat, or even breathe. People with FOP usually lose nearly all mobility by the age of 30. The average lifespan is approximately 40 years. Although the genetic defect for FOP was recently discovered, little is known about the cellular basis of this condition.
In all instances, previous studies have determined that the cause seems to be a "signaling error" to a progenitor cell, a cell that has not yet become completely differentiated and could become one of several different types of mature cells. Progenitor cells usually remain dormant until certain cells die or are damaged and need replacement. For differentiation to be completed, the progenitor cells must receive specific biochemical signals. Those that become bone cells within soft tissue receive an incorrect message about which kind of cell to become.
Frederick S. Kaplan, M.D., Eileen M. Shore, Ph.D., David L. Glaser, M.D., Vitali Lounev, Ph.D., and their colleagues at the University of Pennsylvania School of Medicine, along with David Goldhamer, Ph.D., and his colleagues at the University of Connecticut, set out to identify the cells that contribute to heterotopic ossification. Drs. Kaplan and Goldhamer and their colleagues used two mouse models in an effort to determine which progenitor cells might be receiving the erroneous signal to repair the injured soft tissue by developing into bone.
They examined three types of progenitor cells: precursors for normal skeletal muscle cells; precursors for vascular smooth muscle cells, which make up the blood vessel wall; and precursors for vascular endothelial cells, which under normal circumstances develop as the interior layer of cells that line the blood vessels.
The researchers investigated the reactions of these three types of cells in the mice. They knew that individuals with FOP have a genetic dysregulation of a cellular switch that controls the activity of a particular protein in the presence of inflammatory triggers. By injecting the mice with this protein, or using mice that over-produced this protein at the nerve-muscle junction, they not only demonstrated that abnormal bone formation could be triggered by soft tissue injury and associated inflammation, they also labeled each type of cell so they could identify the progenitor cells involved in the heterotopic ossification process. Skeletal muscle precursor cells and vascular smooth muscle precursor cells showed very little to no indication that they played a role in producing bone in the wrong place. However, the vascular endothelial precursors had a contribution that seemed robust and significant in this abnormal process.
Dr. Kaplan, Dr. Goldhamer, and colleagues published their findings in the Journal of Bone & Joint Surgery. These new insights into the cellular pathophysiology of heterotopic ossification hold promise for therapeutic regulation of specific cell lineages, and thus could lead to future treatment options for this painful condition.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at 301-495-4484 or 877-22-NIAMS (toll-free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
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Reference: Lounev VY, Ramachandran R, Wosczyna MN, Yamamoto M, Maidment ADA, Shore EM, Glaser DL, Goldhamer DJ, Kaplan FS. Identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am. 2009 Mar 1;91(3):652-63. PMID: 19255227.