Antagonizing midkine accelerates fracture healing in mice by enhanced bone formation in the fracture callus

BACKGROUND AND PURPOSE: Previous findings suggest that the growth and differentiation factor midkine (Mdk) is a negative regulator of osteoblast activity and bone formation, thereby raising the possibility that a specific Mdk antagonist might improve bone formation during fracture healing. EXPERIMENTAL APPROACH: In the present study, we investigated the effects of a monoclonal anti‐Mdk antibody (Mdk‐Ab) on bone healing using a standardized femur osteotomy model in mice. Additional in vitro experiments using chondroprogenitor and preosteoblastic cells were conducted to analyse the effects of recombinant Mdk and Mdk‐Ab on differentiation markers and potential binding partners in these cells. KEY RESULTS: We demonstrated that treatment with Mdk‐Ab accelerated bone healing in mice based on increased bone formation in the fracture callus. In vitro experiments using preosteoblastic cells showed that Mdk‐Ab treatment abolished the Mdk‐induced negative effects on the expression of osteogenic markers and Wnt/β‐catenin target proteins, whereas the differentiation of chondroprogenitor cells was unaffected. Phosphorylation analyses revealed an important role for the low‐density lipoproteinLDL receptor‐related protein 6 in Mdk signalling in osteoblasts. CONCLUSIONS AND IMPLICATIONS: We conclude that Mdk‐Ab treatment may be a potential novel therapeutic strategy to enhance fracture healing in patients with orthopaedic complications such as delayed healing or non‐union formation.