High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.
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.
Department of Bioengineering, University of California, Los Angeles, California, USA.
Janette N
JN
Zara
Ronald K
RK
Siu
Xinli
X
Zhang
Jia
J
Shen
Richard
R
Ngo
Min
M
Lee
Weiming
W
Li
Michael
M
Chiang
Jonguk
J
Chung
Jinny
J
Kwak
Benjamin M
BM
Wu
Kang
K
Ting
Chia
C
Soo
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001845:Bone Cysts / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005269:Femur / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000009:adverse effects* / Q000494:pharmacology; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew
C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
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