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BMP9 found as the most potent bone forming factor

By T.-C. He, MD, PhD

Engineering bone tissue can significantly improve human health by restoring bone and skeletal tissue functions that have been compromised by diseases or injuries. Clinical problems that would benefit from engineered bone tissues include bone loss from fractures, non-healing fractures, and/or medical conditions such as tumor resections and infections. In fact, more than 1.6 million bone grafting procedures are performed annually in the United States alone. Since bone has a complex structure and its function requires well-orchestrated interactions between cells, the extracellular matrix, biomechanical forces, as well as gene and protein regulatory factors, successful regeneration of bone tissue requires a multidisciplinary approach involving the integration of materials science, stem cell biology, biomechanical sciences, and translational medicine. At the minimum, successful bone regeneration requires three integral components: osteoprogenitor cells, osteoinductive factors, and osteoconductive scaffolds.

Although many growth factors and signaling molecules play important roles in regulating osteogenic differentiation from mesenchymal stem cells (MSCs), bone morphogenetic proteins (BMPs) are among the most potent osteoinductive factors. Originally isolated as proteins that induce bone and cartilage formation in vivo, BMPs belong to the transforming growth factor β (TGFβ) superfamily and function as multifunctional regulators of proliferation and differentiation during development. The bone regeneration that occurs during fracture repair progresses through sequential phases similar to endochondral ossification, and it is generally postulated that osteogenesis is a sequential multistep cascade that recapitulates most, if not all, of the cellular events that occur during embryonic skeletal development. In 2001, the FDA approved recombinant BMP7 (marketed as OP-1 by Stryker Biotech) under the Humanitarian Device Exemption, for use in long bone non-unions and for recalcitrant non-unions. In 2004, the FDA approved recombinant BMP2 (marketed as Infuse by Medtronic Sofamor Danek) for treating open tibial shaft fractures (but not for use in non-unions).

BMP9 induces the highest activity of osteogenic marker alkaline phosphatase in mesenchymal stem cells in vitro (A). When transduced into the same amount of mesenchymal stem cells, BMP9 induces the most robust ectopic bone formation (arrows) among all five osteogenic BMPs (BMP2 is shown as an example) (B). See Refs. Cheng et al J Bone Joint Surg Am. 85-A(8):1544-52; Kang, et al Gene Therapy 11:1312–1320; and Kang et al Stem Cells and Development 18(4):545-558.

Since there are at least 14 types of BMPs in humans and rodents, a longstanding question has been whether BMP2 and/or BMP7 represent the most efficacious BMPs for bone formation. This question could not be answered easily using BMP recombinant proteins because (1) recombinant BMP proteins are not available for all 14 BMPs; and (2) not all recombinant BMP proteins recapitulate the full spectrums of their biological activities. Our faculty member T.-C. He, MD, PhD, teaming up with Rex C. Haydon, MD, PhD and Hue H. Luu, MD, overcame the above limitations by constructing a panel of recombinant adenoviral vectors expressing the 14 types of BMPs. These vectors enabled the research team to conduct a comprehensive analysis of the osteogenic activities of the 14 BMPs in MSCs. Through their systematic comparison analysis, they found that, for the first time, the previously unnoticed BMP9 exhibits the highest osteogenic activity among the 14 BMPs both in vitro and in vivo, while BMP2 and BMP6, and to a much less extent, BMP4 and BMP7, also have robust bone forming activity (see the figure). Surprisingly, BMP7 exhibits rather weak osteogenic activity in early stage bone progenitors. The research team further found that bone formation induced by BMP9, but not BMP2, BMP6 or BMP7, cannot be blocked by negative regulators such as BMP3 and noggin, which may provide the underlying mechanism for BMP9’s potent osteogenic activity. Dr. He and his colleagues are focusing on the development of safe and economical approaches to moving BMP9 from bench to clinic.

See refs. Cheng et al J Bone Joint Surg Am. 85-A(8):1544-52; Kang, et al Gene Therapy 11:1312–1320; Kang et al Stem Cells and Development 18(4):545-558. For more information, please visit Dr. He’s lab’s homepage: http://www.boneandcancer.org

Dr. He
T.-C. He, MD, PhD, is a tenured Associate Professor and the Director of Molecular Oncology Laboratory in the Department. Dr. He is a well-established investigator with over 250 peer-reviewed publications, which are cited over 30,000 times. He has broad interests in the areas of stem cell biology, cancer biology (especially sarcomas) and regenerative medicine.
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