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

Abstract:

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.

journal_name

Br J Pharmacol

authors

Haffner-Luntzer M,Heilmann A,Rapp AE,Roessler R,Schinke T,Amling M,Ignatius A,Liedert A

doi

10.1111/bph.13503

subject

Has Abstract

pub_date

2016-07-01 00:00:00

pages

2237-49

issue

14

eissn

0007-1188

issn

1476-5381

journal_volume

173

pub_type

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