Takashi Kaito1, Tokimitsu Morimoto2, Yuki Mori3, Sadaaki Kanayama2, Takahiro Makino2, Shota Takenaka2, Yusuke Sakai2, Satoru Otsuru4, Yoshichika Yoshioka3, Hideki Yoshikawa2. 1. Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan. Electronic address: takashikaito@ort.med.osaka-u.ac.jp. 2. Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan. 3. Biofunctional imaging, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Center for Information and Neural Networks, National Institute of Information and Communications Technology and Osaka University, 1-4 Yamadaoka, Suita, Osaka 565-0871, Japan. 4. Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
Abstract
BACKGROUND CONTEXT: Bone morphogenetic protein (BMP)-2/7 heterodimer is a stronger inducer of bone regeneration than individual homodimers. However, clinical application of its potent bone induction ability may be hampered if its use is accompanied by excessive inflammatory reactions. PURPOSE: We sought to quantitatively evaluate bone induction and inflammatory reactions by BMP heterodimer and corresponding BMP homodimers using ultra-high resolution magnetic resonance imaging (MRI) and micro-computed tomography. STUDY DESIGN: An experimental animal study was carried out. METHODS: A total of 32 absorbable collagen sponge implantations into dorsal muscle were performed in rats of four different groups (control group, 0 µg BMP; recombinant human (rh)BMP-7 group, 3 µg rhBMP-7; rhBMP-2 group, 3 µg rhBMP-2; rhBMP-2/7 group, 3 µg rhBMP-2/7). Inflammatory reactions were evaluated by 11.7-T MRI (axial T2-weighted imaging using rapid acquisition with relaxation enhancement) at postoperative days 2 and 7. Bone volumes (BVs) of the induced ectopic bone were quantified at postoperative day 7. In addition, immunohistochemical staining for interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α was performed in samples obtained on postoperative day 2. Bone formation (BF)-to-inflammation (IM) ratios were calculated by dividing BVs by values of inflamed areas. RESULTS: At postoperative day 2, the mean volume of T2 high area on MRI scans in BMP-2 group was significantly larger than that in control group. In contrast, the BMP-2/7 had no difference in the mean volume of T2 high area compared with the control group; however, there was no difference between the BMP-2/7 compared with BMP-2 group. At postoperative day 7, the volumes of T2 high area were not different between the groups. Mean BV of the newly formed bone on postoperative day 7 was significantly greater in BMP-2/7 group than in BMP-7 groups. No new bone formation was observed in control group. BF-to-IM ratio in BMP-2/7 group was significantly higher than those in BMP-2 and BMP-7 homodimer groups. Immunohistochemistry experiments did not reveal differences in expression levels of IL-1β, IL-6, or TNF-α in samples from BMP-2, BMP-7, and BMP-2/7 groups. CONCLUSIONS: This study demonstrated that BMP-2/7 heterodimer has stronger bone induction ability without accompanying increased inflammatory reactions (the increased BF-to-IM ratio) than those observed by BMP-2 or BMP-7 homodimers. These results suggest that BMP-2/7 heterodimer can be an alternative to BMP-2 and BMP-7 homodimers in clinical applications, although further translational studies, including whether lower doses of BMP heterodimer may produce similar bone formation compared with the BMP homodimers but produce a reduced inflammatory response, are required.
BACKGROUND CONTEXT: Bone morphogenetic protein (BMP)-2/7 heterodimer is a stronger inducer of bone regeneration than individual homodimers. However, clinical application of its potent bone induction ability may be hampered if its use is accompanied by excessive inflammatory reactions. PURPOSE: We sought to quantitatively evaluate bone induction and inflammatory reactions by BMP heterodimer and corresponding BMP homodimers using ultra-high resolution magnetic resonance imaging (MRI) and micro-computed tomography. STUDY DESIGN: An experimental animal study was carried out. METHODS: A total of 32 absorbable collagen sponge implantations into dorsal muscle were performed in rats of four different groups (control group, 0 µg BMP; recombinant human (rh)BMP-7 group, 3 µg rhBMP-7; rhBMP-2 group, 3 µg rhBMP-2; rhBMP-2/7 group, 3 µg rhBMP-2/7). Inflammatory reactions were evaluated by 11.7-T MRI (axial T2-weighted imaging using rapid acquisition with relaxation enhancement) at postoperative days 2 and 7. Bone volumes (BVs) of the induced ectopic bone were quantified at postoperative day 7. In addition, immunohistochemical staining for interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α was performed in samples obtained on postoperative day 2. Bone formation (BF)-to-inflammation (IM) ratios were calculated by dividing BVs by values of inflamed areas. RESULTS: At postoperative day 2, the mean volume of T2 high area on MRI scans in BMP-2 group was significantly larger than that in control group. In contrast, the BMP-2/7 had no difference in the mean volume of T2 high area compared with the control group; however, there was no difference between the BMP-2/7 compared with BMP-2 group. At postoperative day 7, the volumes of T2 high area were not different between the groups. Mean BV of the newly formed bone on postoperative day 7 was significantly greater in BMP-2/7 group than in BMP-7 groups. No new bone formation was observed in control group. BF-to-IM ratio in BMP-2/7 group was significantly higher than those in BMP-2 and BMP-7 homodimer groups. Immunohistochemistry experiments did not reveal differences in expression levels of IL-1β, IL-6, or TNF-α in samples from BMP-2, BMP-7, and BMP-2/7 groups. CONCLUSIONS: This study demonstrated that BMP-2/7 heterodimer has stronger bone induction ability without accompanying increased inflammatory reactions (the increased BF-to-IM ratio) than those observed by BMP-2 or BMP-7 homodimers. These results suggest that BMP-2/7 heterodimer can be an alternative to BMP-2 and BMP-7 homodimers in clinical applications, although further translational studies, including whether lower doses of BMP heterodimer may produce similar bone formation compared with the BMP homodimers but produce a reduced inflammatory response, are required.
Authors: Samantha G Maliha; Christopher D Lopez; Paulo G Coelho; Lukasz Witek; Madison Cox; Alan Meskin; Sejndi Rusi; Andrea Torroni; Bruce N Cronstein; Roberto L Flores Journal: Plast Reconstr Surg Date: 2020-02 Impact factor: 5.169
Authors: Maria Catalina Gomez-Puerto; Prasanna Vasudevan Iyengar; Amaya García de Vinuesa; Peter Ten Dijke; Gonzalo Sanchez-Duffhues Journal: J Pathol Date: 2018-11-27 Impact factor: 7.996