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  • Author or Editor: David F. Kallmes x
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Gregory A. Helm, Jin Zhong Li, Tord D. Alden, Sarah B. Hudson, Elisa J. Beres, Mary Cunningham, Mark M. Mikkelsen, Debra D. Pittman, Kelvin M. Kerns and David F. Kallmes

Object. Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that have attracted the greatest interest. Expression of the BMP-13 gene is predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/neoligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector.

Methods. Athymic nude rats were injected with 3.75 × 1010 plaque-forming units of adenovirus (Ad)-BMP-13 or Ad-β-galactosidase in the thigh musculature, and the region was examined using light and electron microscopy at various time points between 2 days and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the treated tissue displayed the histological and ultrastructural appearance of neotendon/neoligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the treated tissue. A short-term bromodeoxyuridine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection. At all time points, the control AD-β-gal injection sites were found to contain only normal muscle, without evidence of inflammation or mesenchymal cell proliferation.

Conclusions. The results of this study indicate that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.

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Gregory A. Helm, Jin Zhong Li, Tord D. Alden, Sarah A. Hudson, Elisa J. Beres, Mary Cunningham, Mark M. Mikkelsen, Debra D. Pittman, Kelvin M. Kerns and David F. Kallmes

Object

Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that has attracted the greatest interest. Expression of the BMP-13 gene has been shown to be predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/ligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector.

Methods

Athymic nude rats were injected with 3.75 × 1010 plaque-forming unit adenovirus (Ad)-BMP-13 or Ad-β-galactosidase in the thigh musculature, and the regions examined using light and electron microscopy at various time points between 2 and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the induced tissue had the histological and ultrastructural appearance of neotendon/ligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the induced tissue. A short-term bromodeoxyuri-dine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection.

Conclusions

The results of this study suggest that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.