Abstract
Impaired bone homeostasis caused by osteomyelitis provokes serious variations in the bone remodeling process, thereby involving multiple inflammatory cytokines to activate bone healing. We have previously established a mouse model for post-traumatic osteomyelitis and studied bone regeneration after sufficient debridement. Moreover, we could further characterize the postinfectious inflammatory state of bony defects after debridement with elevated osteoclasts and decreased bone formation despite the absence of bacteria. In this study, we investigated the positive effects of Wnt-pathway modulation on bone regeneration in our previous established mouse model. This was achieved by local application of Wnt3a, a recombinant activator of the canonical Wnt-pathway. Application of Wnt3a could enhance new bone formation, which was verified by histological and μ-CT analysis. Moreover, histology and western blots revealed enhanced osteoblastogenesis and downregulated osteoclasts in a RANKL-dependent manner. Further analysis of Wnt-pathway showed downregulation after bone infections were reconstituted by application of Wnt3a. Interestingly, Wnt-inhibitory proteins Dickkopf 1 (DKK1), sclerostin, and secreted frizzled protein 1 (sFRP1) were upregulated simultaneously to Wnt-pathway activation, indicating a negative feedback for active form of Beta-catenin. In this study, we could demonstrate enhanced bone formation in defects caused by post-traumatic osteomyelitis after Wnt3a application.Key messagesOsteomyelitis decreases bone regenerationWnt3a restores bone healing after infectionCanonical Wnt-pathway activation with negative feedback
Highlights
Johannes Maximilian Wagner and Felix Reinkemeier contributed to this work.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.One of the main evolutionary driving forces in humans is the capability to combat infections
Canonical Wnt-pathway is downregulated in postinfectious inflammatory state
Elevated osteoblastogenesis and mature osteoblasts could be observed in runtrelated transcription factor 2 (Runx2) and osteocalcin staining (Fig. 2B), as well as western blots (Fig. 3)
Summary
Johannes Maximilian Wagner and Felix Reinkemeier contributed to this work. One of the main evolutionary driving forces in humans is the capability to combat infections. In this context, bone infections are of particular interest and need special attention as they pose one of the biggest problems in orthopedic surgery especially after open fractures of long bones [1]. The incidence of osteomyelitis (OM) in elective bone surgery is considered to be 1–5%. OM still occurs in 5–30% of open fractures, depending mainly on the severity of the fracture [1]
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