BMP-7-induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6-mice.
Nonsteroidal antiinflammatory drugs (NSAIDs) are known to potentially impair the fracture healing process. The aim of the present study was to determine if the impairment of bone healing by systemic NSAID application is, at least in part, due to an interaction of NSAIDs with the bone anabolic BMP-7 pathway. Therefore, we first analyzed fracture healing in control and diclofenac-treated mice, where we not only found a significant impairment of fracture healing due to diclofenac treatment as assessed by biomechanical testing and microCT imaging, but also found high coexpression of bone morphogenetic protein-7 (BMP-7) and cyclooxygenase-2 (COX-2) within the fracture callus of both groups. To experimentally address the possible interaction between BMP-7 and COX-2, we then induced ectopic bone formation in control (n = 10) and diclofenac-treated mice (n = 10) by application of BMP-7 (recombinant human OP-1, rhOP-1) into the hamstring muscles. After 20 days of treatment, each ectopic bone nodule was analyzed by contact-radiography, microCT, histology, and histomorphometry. Diclofenac application decreased the trabecular number and bone mass in the ectopic bone nodules significantly due to reduced osteoblast number and activity. These data demonstrate that the bone anabolic effect of BMP-7 and fracture healing is impaired by diclofenac application, and suggest that the potential negative impact of NSAIDs on fracture healing is, at least in part, due to interference with BMP-7 signaling.
Spiro
Alexander S
AS
Department of Trauma-, Hand-, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Beil
F Timo
FT
Baranowsky
Anke
A
Barvencik
Florian
F
Schilling
Arndt F
AF
Nguyen
Khoa
K
Khadem
Shahram
S
Seitz
Sebastian
S
Rueger
Johannes M
JM
Schinke
Thorsten
T
Amling
Michael
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000502:physiology; D004008:Diclofenac / Q000633:toxicity*; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D055419:Bone Morphogenetic Protein 7; D011994:Recombinant Proteins; D004008:Diclofenac; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2