Antagonizing midkine accelerates fracture healing in mice by enhanced bone formation in the fracture callus
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Antagonizing midkine accelerates fracture healing in mice by enhanced bone formation in the fracture callus. / Haffner-Luntzer, Melanie; Heilmann, Aline; Rapp, Anna Elise; Roessler, Robin; Schinke, Thorsten; Amling, Michael; Ignatius, Anita; Liedert, Astrid.
in: BRIT J PHARMACOL, Jahrgang 173, Nr. 14, 07.2016, S. 2237-49.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Antagonizing midkine accelerates fracture healing in mice by enhanced bone formation in the fracture callus
AU - Haffner-Luntzer, Melanie
AU - Heilmann, Aline
AU - Rapp, Anna Elise
AU - Roessler, Robin
AU - Schinke, Thorsten
AU - Amling, Michael
AU - Ignatius, Anita
AU - Liedert, Astrid
N1 - © 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2016/7
Y1 - 2016/7
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1111/bph.13503
DO - 10.1111/bph.13503
M3 - SCORING: Journal article
C2 - 27111560
VL - 173
SP - 2237
EP - 2249
JO - BRIT J PHARMACOL
JF - BRIT J PHARMACOL
SN - 0007-1188
IS - 14
ER -