High Doses of Bone Morphogenetic Protein 2 Induce Structurally Abnormal Bone and Inflammation In Vivo
Open accessAbstract
The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.
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Clinical use of osteoinductive factors such as BMP-2 and BMP-9 is associated with side effects including ectopic bone formation, inflammation, bone resorption, and hematoma.
“However, increasing side effects are reported during the clinical use of osteoinductive factors, such as ectopic bone formation, inflammation, bone resorption, and hematoma [11].”
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- Authors
- Zara, J. N., Siu, R. K., Zhang, X., Shen, J., Ngo, R., Lee, M., Li, W., Chiang, M., Chung, J., Kwak, J., Wu, B. M., Ting, K., & Soo, C.
- Affiliations
- University of California, Los Angeles (US)
- Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, California.
- Corresponding author
- Soo, Chia
- Venue
- Tissue Engineering Part A
- Publisher
- SAGE Publications
- Published
- 2011-05
- Volume
- 17
- Issue
- 9-10
- Pages
- 1389-1399
- ISSN
- 1937-3341 (ISSN-L)
- 1937-335X
- PMC
- PMC3079169
- OpenAlex
- W2033954341
- Cited by
- 560
- References
- 53
- Citations by year
- 2026: 30 · 2025: 29 · 2024: 27 · 2023: 32 · 2022: 46 · 2021: 37 · 2020: 41 · 2019: 50 · 2018: 55 · 2017: 50 · 2016: 33 · 2015: 44 · 2014: 41 · 2013: 24 · 2012: 17
- FWCI
- 16.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Tissue Engineering Part A (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (10677)
- U.S. Army
- National Institute of Dental and Craniofacial Research (R21 DE0177711, R01 DE16107-05S1, DE01607-01, R21 DE0177711-01, R01DE016107)
- U.S. Army Medical Research Acquisition Activity
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
- Keywords
- BMP-2, soft tissue swelling, segmental bone defect, inflammation, osteoclast-like cells, adipose tissue, bone fusion
- MeSH terms
- Adipose Tissue, Animals, Bone Cysts, Disease Models, Animal, Femoral Fractures, Femur, Humans, Male, Osteogenesis, Rats, Inbred Lew, Matrix Metalloproteinase 2, Rats
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