Study of bone morphogenetic proteins wins Vaughan Award
By Joen Kinnan
Tong-Chuan He, MD, PhD, and Rex C. Haydon, MD, PhD, received the 2006 Kappa Delta Ann Donor Vaughan Award for their paper titled “The Distinct Roles of Bone Morphogenetic Proteins in Mesenchymal Stem Cell Differentiation.”
Rex C. Haydon, MD, PhD, and Tong-Chuan He, MD, PhD.
With this paper, Drs. He and Haydon have significantly enhanced the understanding of the role played by bone morphogenetic proteins (BMPs) during stem cell differentiation, in particular, during osteogenic differentiation. Their work also builds a scientific foundation for the appropriate and efficacious use of BMPs in clinical applications. As Dr. He explained, “The research described in the manuscript has direct clinical relevance in that it supplies critical insight into the cellular and molecular mechanisms underlying individual BMP activity.”
Bone morphogenetic proteins are a family of structurally homologous morphogens that mediate the differentiation of mesenchymal stem cells into bone, cartilage, tendons and ligaments, fat, and other components of connective tissue. Other authors presented earlier documentation of the osteogenic potential of two BMPs: rhBMP2 and rhBMP7/OP-1, and researchers soon began to use them in clinical applications. However, as Dr. He wrote, “Prior to the work described in this manuscript, no comprehensive analysis had ever been undertaken to characterize the relative activity of all BMPs.” This new information will make it possible to select the optimal BMP for many different clinical applications.
Drs. He and Haydon constructed recombinant adenoviruses expressing each of the 14 BMPs (AdBMPs) in order to study the relative activity of each BMP during mesenchymal stem cell differentiation, both in vitro and in vivo. Through expression profile analysis of osteogenic BMPs versus nonosteogenic BMPs, the authors discovered that osteogenic BMPs regulate a distinct set of downstream target genes in the early stages of osteogenic differentiation.
“In fact, we have recently demonstrated that some of these target genes function as important mediators of osteogenic BMP signaling, and their expression must be tightly regulated,” they wrote.
Bone healing is one area that could be dramatically affected by this new research. Patients with segmental bone loss, fracture nonunion and failed spinal fusion face pain, disability and an altogether gloomy prognosis when bone fails to heal itself. A reliable method to promote bone regeneration in recalcitrant cases could well revolutionize the clinical management of these and other musculoskeletal disorders. Clinical studies using recombinant human BMP2 and BMP7 have been somewhat promising, but their efficacy is unpredictable, and the cost of production is high.
This research opens new possibilities. The authors determined that BMPs 2, 6 and 9—and to a lesser extent BMP4 and BMP7—represent the most osteogenic BMPs, both in vitro and in vivo. The findings about the osteogenic activity of BMP9 should spark particular interest, because little is known about its biological functions.
Drs. He and Haydon also concluded that some BMPs apparently have a synergistic effect on osteogenic differentiation and that osteogenic BMPs produce distinct molecular fingerprints. According to the authors, “It is conceivable that osteogenic BMPs (BMPs 2, 4, 6, 7 and 9) may be used to formulate synergistic pairs among themselves and/or with other less osteogenic BMPs for efficacious bone regeneration.”
This work also opens avenues to a better understanding of the pathogenesis of bone diseases, such as primary bone tumors or osteosarcomas. Osteosarcoma cells often exhibit osteoblast-like features. This behavior suggests that there may be defects in the osteogenic terminal differentiation in these tumor cells.
Future BMP research
Though this is a major study, which took nearly six years to complete, there is more work to be done in this area. “At the basic science front, we need to further investigate the molecular mechanisms behind BMPs, especially BMP9, and the differentiation of mesenchymal stem cells,” said the authors.
“Our results and other recent reports suggest that BMPs may play an important role in regulating lineage commitment and terminal differentiation of mesenchymal stem cells. We found that BMPs can induce multiple lineage-specific markers in mesenchymal stem cells, including osteogenic (Runx2), chondrogenic (Sox9), adipogenic (PPARg2), and myogenic (MyoD). Thus, future investigation should also be directed at understanding how different lineage-specific differentiation occurs in mesenchymal stem cells and the role of BMPs in that process,” they report.
On the clinical research side, Drs. He and Haydon suggest that the synergistic osteogenic activity of different BMPs need to be explored to find the most efficacious combinations for osteogenic treatment cocktails. In addition, alternative nonviral and/or safer gene delivery approaches would broaden the clinical use of BMPs.
One promising trend is to use cell-based gene therapy, according to the authors. They suggest that this is probably most suitable for osteogenic BMP gene therapy because marrow stem cells and other sources of osteoblast progenitor cells can easily be prepared from—and for—individual patients. As the authors concluded, ”Osteogenic BMPs hold great promise for regenerative medicine.”
Both authors are assistant professors in the department of surgery at the University of Chicago.