High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.

Abstract

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.

• Authors: Janette N Zara, Ronald K Siu, Xinli Zhang, Jia Shen, Richard Ngo, Min Lee, Weiming Li, Michael Chiang, Jonguk Chung, Jinny Kwak, Benjamin M Wu, Kang Ting, Chia Soo
• Journal: Tissue engineering. Part A (Tissue Eng Part A) Vol. 17 Issue 9-10 Pg. 1389-99 (May 2011) ISSN: 1937-335X [Electronic] United States
• PMID: 21247344 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• MMP2 protein, human
• Matrix Metalloproteinase 2

Topics

• Adipose Tissue (metabolism, pathology)
• Animals
• Bone Cysts (chemically induced, metabolism, pathology)
• Disease Models, Animal
• Femoral Fractures (metabolism, pathology, therapy)
• Femur (metabolism, pathology)
• Humans
• Male
• Matrix Metalloproteinase 2 (adverse effects, pharmacology)
• Osteogenesis (drug effects)
• Rats
• Rats, Inbred Lew