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



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.



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.



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.
Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Melanie
0000-0002-3333-2613
M
Haffner-Luntzer
Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Aline
A
Heilmann
Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Anna Elise
AE
Rapp
Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Robin
R
Roessler
Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Thorsten
T
Schinke
Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Michael
M
Amling
Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Anita
A
Ignatius
Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Astrid
A
Liedert
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002146:Bony Callus / Q000187:drug effects* / Q000254:growth & development; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000078792:Midkine; D010012:Osteogenesis / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D000078792:Midkine