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University of Pittsburgh Schools of the Health Sciences

Gene Silencing Succeeds In Directing Muscle-Derived Stem Cells To Become Bone-Forming Cells

BALTIMORE, June 1, 2006 — Using a relatively new technology called RNA interference to turn off genes that regulate cell differentiation, University of Pittsburgh researchers have demonstrated they can increase the propensity of muscle-derived stem cells (MDSCs) to become bone-forming cells. Based on these results, the investigators believe that by turning off specific genetic factors they can control the capacity of MDSCs as a means of treating various musculoskeletal diseases and injuries.

RNA interference is a simple yet powerful technique that uses short interfering RNAs (siRNAs) – small molecules that prevent a gene from being expressed – to turn off the production of specific proteins in a cell. In their study, the Pitt researchers generated siRNAs to two mouse genes: MyoD1, a master gene that regulates the formation of muscle cells or fibers (myogenesis), and Smad6, which encodes a molecule that specifically inhibits a cell’s ability to respond to bone-forming, or osteogenic, signals.

When the researchers examined cultured cells in which myogenesis was inhibited, they found a significant increase in the cells’ bone-forming potential. However, contrary to their expectations, the researchers did not observe any bone formation when the cells were implanted in skeletal muscle. Yet, when they turned off ostegenic inhibition in these same cells using Smad6 siRNA prior to implanting them in mice, 60 percent of the mice developed radiologically detectable bone within three weeks.

“By understanding the genetic mechanisms that regulate a cell’s propensity to differentiate into one type of cell line over another, we may be able to regulate their ability to generate bone for the treatment of various diseases and injuries of the musculoskeletal system, such as osteoporosis or severe fractures,” said first author Jonathan B. Pollett, Ph.D., research associate, department of orthopaedic surgery, Children’s Hospital of Pittsburgh. Corresponding author Johnny Huard, Ph.D., the Henry J. Mankin Endowed Chair in Orthopaedic Surgery Research, University of Pittsburgh School of Medicine, and Director of the Stem Cell Research Center (SCRC) of Children’s Hospital of Pittsburgh, added that muscle and bone injuries are very frequent in sports medicine and this research may someday significantly improve the treatment of such problems.

Others involved in this study include, Jessica Tebbets, Bridget M. Deasy, Ph.D., and Karin A. Corsi of the SCRC of Children s Hospital of Pittsburgh.

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