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BMP-7-induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6-mice
Alexander S Spiro1, F Timo Beil, Anke Baranowsky
1Department of Trauma-, Hand-, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract:
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.
Insights
Nonsteroidal anti-inflammatory drugs (NSAIDs) impair fracture healing by interfering with the bone morphogenetic protein-7 (BMP-7) pathway. Diclofenac, an NSAID, reduced BMP-7
Area of Science:
- Orthopedics
- Pharmacology
- Regenerative Medicine
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with impaired fracture healing.
- The bone morphogenetic protein-7 (BMP-7) pathway is crucial for bone formation and repair.
- The interaction between NSAIDs and the BMP-7 pathway in fracture healing remains incompletely understood.
Purpose of the Study:
- To investigate whether NSAID-induced impairment of bone healing involves the BMP-7 pathway.
- To determine if diclofenac interferes with the bone anabolic effects of BMP-7.
Main Methods:
- Fracture healing was assessed in control and diclofenac-treated mice using biomechanical testing and microCT imaging.
- Coexpression of BMP-7 and cyclooxygenase-2 (COX-2) was analyzed in fracture calluses.
- Ectopic bone formation was induced by BMP-7 application in control and diclofenac-treated mice and analyzed via radiography, microCT, histology, and histomorphometry.
Main Results:
- Diclofenac treatment significantly impaired fracture healing in mice.
- High coexpression of BMP-7 and COX-2 was observed in fracture calluses.
- Diclofenac application reduced trabecular number and bone mass in BMP-7-induced ectopic bone, correlating with decreased osteoblast activity.
Conclusions:
- NSAID (diclofenac) application impairs the bone anabolic effects of BMP-7.
- The negative impact of NSAIDs on fracture healing may be partly due to interference with BMP-7 signaling.
- This study elucidates a molecular mechanism underlying NSAID-induced bone healing deficits.
