Enhancement of Bone Morphogenetic Protein-2-Induced Ectopic Bone Formation by Transforming Growth Factor-β1

• Published in: Tissue engineering. Part A 2011-03, Vol.17 (5-6), p.597-606
• Main Authors: Tachi, Keita, Takami, Masamichi, Sato, Hana, Mochizuki, Ayako, Zhao, Baohong, Miyamoto, Yoichi, Tsukasaki, Hiroaki, Inoue, Tomio, Shintani, Satoru, Koike, Tatsuya, Honda, Yoshitomo, Suzuki, Osamu, Baba, Kazuyoshi, Kamijo, Ryutaro
• Format: Article
• Language: English
• Subjects: Animals; Bone Morphogenetic Protein 2 - pharmacology; Bone morphogenetic proteins; Bone Regeneration - drug effects; Bones; Cell Count; Cell Differentiation - drug effects; Choristoma - pathology; Growth; Humans; Mice; Organ Size - drug effects; Original Articles; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoclasts - cytology; Osteoclasts - drug effects; Osteogenesis - drug effects; Physiological aspects; Radiography; Skull - diagnostic imaging; Skull - drug effects; Skull - pathology; Time Factors; Transforming Growth Factor beta1 - pharmacology; Transforming growth factors
• ISSN: 1937-3341; 1937-335X
• DOI: 10.1089/ten.tea.2010.0094

Bone morphogenetic proteins (BMPs) possess osteoinductive activities and are useful for clinical treatments, including bone regeneration. We found that transforming growth factor (TGF)-β1 strongly enhances the osteoinductive activity of BMP-2. Collagen sponges containing 5 μg of BMP-2 were implanted into mouse muscle tissues, after which lump-like masses appeared and grew until day 7. Subsequently, calcification occurred in the lump-like masses by day 14. Addition of 50 ng of TGF-β1 to the BMP-2-containing sponges markedly accelerated the growth of the lump-like masses and resulted in a fivefold increase in total bone volume as compared with BMP-2 alone. The number of osteoblasts in ectopic bone tissues at 14 days after implantation induced by BMP-2+TGF-β1 was twofold greater than that with BMP-2 alone, whereas the number of osteoclasts was decreased by half. On the other hand, TGF-β1 accelerated the differentiation of both osteoblasts and osteoclasts in the early stage (2–7 days after implantation) of ectopic bone formation. We also implanted collagen sponges into bone defects surgically created in mouse calvaria. Sponges containing 2.5 μg of BMP-2 and 25 ng of TGF-β1 caused complete filling of the defects with orthotopic bone, whereas those containing 2.5 μg of BMP-2 alone caused only partial filling. These results suggest that TGF-β1 enhances BMP-2-induced ectopic bone formation by accelerating the growth of lump-like masses, and regulates osteoblast and osteoclast generation. Our findings may contribute to the development of a new treatment method for skeletal disorders.