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Spine J. 2018 Jan;18(1):139-146. doi: 10.1016/j.spinee.2017.07.171. Epub 2017 Jul 20.

BMP-2/7 heterodimer strongly induces bone regeneration in the absence of increased soft tissue inflammation.

Author information

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.

KEYWORDS:

Bone induction; Bone morphogenetic protein; Heterodimer; Inflammation; Magnetic resonance imaging; Micro-computed tomography

PMID:
28735764
DOI:
10.1016/j.spinee.2017.07.171
[Indexed for MEDLINE]

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