title: Inhibition of Midkine Augments Osteoporotic Fracture Healing.
abstract: The heparin-binding growth and differentiation factor midkine (Mdk) is proposed to negatively regulate osteoblast activity and bone formation in the adult skeleton. As Mdk-deficient mice were protected from ovariectomy (OVX)-induced bone loss, this factor may also play a role in the pathogenesis of postmenopausal osteoporosis. We have previously demonstrated that Mdk negatively influences bone regeneration during fracture healing. Here, we investigated whether the inhibition of Mdk using an Mdk-antibody (Mdk-Ab) improves compromised bone healing in osteoporotic OVX-mice. Using a standardized femur osteotomy model, we demonstrated that Mdk serum levels were significantly enhanced after fracture in both non-OVX and OVX-mice, however, the increase was considerably greater in osteoporotic mice. Systemic treatment with the Mdk-Ab significantly improved bone healing in osteoporotic mice by increasing bone formation in the fracture callus. On the molecular level, we demonstrated that the OVX-induced reduction of the osteoanabolic beta-catenin signaling in the bony callus was abolished by Mdk-Ab treatment. Furthermore, the injection of the Mdk-Ab increased trabecular bone mass in the skeleton of the osteoporotic mice. These results implicate that antagonizing Mdk may be useful for the therapy of osteoporosis and osteoporotic fracture-healing complications.
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Haffner-Luntzer
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kemmler
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Heidler
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Prystaz
authors.affiliation: Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.affiliation: Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kovtun
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Rapp
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
authors.affiliation: Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Liedert
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001861:Bone Regeneration / Q000502:physiology*; D002146:Bony Callus / Q000378:metabolism*; D000071556:Cancellous Bone / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D000078792:Midkine; D010012:Osteogenesis / Q000502:physiology; D010024:Osteoporosis / Q000473:pathology / Q000628:therapy; D058866:Osteoporotic Fractures / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000906:Antibodies; D016207:Cytokines; D051176:beta Catenin; D000078792:Midkine