Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect |
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| Affiliation: | 1. Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA;2. Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, University of Connecticut Health, Farmington, CT, USA;3. Phylon Pharma Services, Newbury Park, CA, USA;4. Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA;1. Faculty of Dentistry, McGill University, Montreal, Quebec H3A 0C7, Canada;2. Faculty of Medicine, McGill University, Montreal, Quebec H3G 1Y6, Canada;3. Genetics Unit, Shriners Hospital for Children, Montreal, Quebec H3G 1A6, Canada;1. Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Republic of Korea;2. Department of Preventive Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea;1. Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia;2. Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia;3. Faculty of Medicine, University of NSW, Kensington, Sydney, NSW 2052, Australia;4. School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA 6009, Australia;1. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;2. School of Dentistry, Department of Oral and Craniofacial Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA |
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| Abstract: | Recombinant human BMP-2 (rhBMP-2) is a potent osteoinductive agent, but has been associated not only with bone formation, but also osteoclastogenesis and bone resorption. Osteoprotegerin (OPG) is a RANKL inhibitor that blocks differentiation and function of osteoclasts. We hypothesized that the combination of local BMP-2 (recombinant protein or a product of gene therapy) plus systemic OPG-Fc is more effective than BMP-2 alone in promoting bone repair. To test this hypothesis we used a mouse critical-sized femoral defect model. Col2.3eGFP (osteoblastic marker) male mice were treated with rhBMP-2 (group I), rhBMP-2 and systemic OPG (group II), rhBMP-2 and delayed administration of OPG (group III), mouse BM cells transduced with a lentiviral vector containing the BMP-2 gene (LV-BMP-2; group IV), LV-BMP-2 and systemic OPG (group V), a carrier alone (group VI) and administration of OPG alone (group VII). All bone defects treated with BMP-2 (alone or combined with OPG) healed, whereas minimal bone formation was noted in animals treated with the carrier alone or OPG alone. MicroCT analysis showed that bone volume (BV) in rhBMP-2 + OPG and LV-BMP-2 + OPG groups was significantly higher compared to rhBMP-2 alone (p < 0.01) and LV-BMP-2 alone (p < 0.001). Similar results were observed in histomorphometry, with rhBMP-2 alone defects exhibiting significantly lower bone area (B.Ar) compared to rhBMP-2 + OPG defects (p < 0.005) and LV-BMP-2 defects having a significantly lower B.Ar compared to all BMP-2 + OPG treated groups (p ≤ 0.01). TRAP staining demonstrated a major osteoclast response in the groups that did not receive OPG (rhBMP-2, LV-BMP-2 and sponge alone) beginning as early as 7 days post-operatively. In conclusion, we demonstrated that locally delivered BMP-2 (recombinant protein or gene therapy) in combination with systemically administered OPG improved bone healing compared to BMP-2 alone in a mouse critical-sized bone defect. These data indicate that osteoclasts can diminish healing responses to BMP-2 and that RANKL inhibition may thus accentuate BMP-2 efficacy. |
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