Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice

The growth and differentiation factor midkine (Mdk) plays an important role in bone development and remodeling. Mdk-deficient mice display a high bone mass phenotype when aged 12 and 18 months. Furthermore, Mdk has been identified as a negative regulator of mechanically induced bone formation and it...

Full description

Bibliographic Details
Main Authors:	Haffner-Luntzer, Melanie, Heilmann, Aline, Rapp, Anna Elise, Beie, Simon, Schinke, Thorsten, Amling, Michael, Ignatius, Anita, Liedert, Astrid
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281158/

id	pubmed-4281158
recordtype	oai_dc
spelling	pubmed-42811582015-01-07 Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice Haffner-Luntzer, Melanie Heilmann, Aline Rapp, Anna Elise Beie, Simon Schinke, Thorsten Amling, Michael Ignatius, Anita Liedert, Astrid Research Article The growth and differentiation factor midkine (Mdk) plays an important role in bone development and remodeling. Mdk-deficient mice display a high bone mass phenotype when aged 12 and 18 months. Furthermore, Mdk has been identified as a negative regulator of mechanically induced bone formation and it induces pro-chondrogenic, pro-angiogenic and pro-inflammatory effects. Together with the finding that Mdk is expressed in chondrocytes during fracture healing, we hypothesized that Mdk could play a complex role in endochondral ossification during the bone healing process. Femoral osteotomies stabilized using an external fixator were created in wildtype and Mdk-deficient mice. Fracture healing was evaluated 4, 10, 21 and 28 days after surgery using 3-point-bending, micro-computed tomography, histology and immunohistology. We demonstrated that Mdk-deficient mice displayed delayed chondrogenesis during the early phase of fracture healing as well as significantly decreased flexural rigidity and moment of inertia of the fracture callus 21 days after fracture. Mdk-deficiency diminished beta-catenin expression in chondrocytes and delayed presence of macrophages during early fracture healing. We also investigated the impact of Mdk knockdown using siRNA on ATDC5 chondroprogenitor cells in vitro. Knockdown of Mdk expression resulted in a decrease of beta-catenin and chondrogenic differentiation-related matrix proteins, suggesting that delayed chondrogenesis during fracture healing in Mdk-deficient mice may be due to a cell-autonomous mechanism involving reduced beta-catenin signaling. Our results demonstrated that Mdk plays a crucial role in the early inflammation phase and during the development of cartilaginous callus in the fracture healing process. Public Library of Science 2014-12-31 /pmc/articles/PMC4281158/ /pubmed/25551381 http://dx.doi.org/10.1371/journal.pone.0116282 Text en © 2014 Haffner-Luntzer et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Haffner-Luntzer, Melanie Heilmann, Aline Rapp, Anna Elise Beie, Simon Schinke, Thorsten Amling, Michael Ignatius, Anita Liedert, Astrid
spellingShingle	Haffner-Luntzer, Melanie Heilmann, Aline Rapp, Anna Elise Beie, Simon Schinke, Thorsten Amling, Michael Ignatius, Anita Liedert, Astrid Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice
author_facet	Haffner-Luntzer, Melanie Heilmann, Aline Rapp, Anna Elise Beie, Simon Schinke, Thorsten Amling, Michael Ignatius, Anita Liedert, Astrid
author_sort	Haffner-Luntzer, Melanie
title	Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice
title_short	Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice
title_full	Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice
title_fullStr	Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice
title_full_unstemmed	Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice
title_sort	midkine-deficiency delays chondrogenesis during the early phase of fracture healing in mice
description	The growth and differentiation factor midkine (Mdk) plays an important role in bone development and remodeling. Mdk-deficient mice display a high bone mass phenotype when aged 12 and 18 months. Furthermore, Mdk has been identified as a negative regulator of mechanically induced bone formation and it induces pro-chondrogenic, pro-angiogenic and pro-inflammatory effects. Together with the finding that Mdk is expressed in chondrocytes during fracture healing, we hypothesized that Mdk could play a complex role in endochondral ossification during the bone healing process. Femoral osteotomies stabilized using an external fixator were created in wildtype and Mdk-deficient mice. Fracture healing was evaluated 4, 10, 21 and 28 days after surgery using 3-point-bending, micro-computed tomography, histology and immunohistology. We demonstrated that Mdk-deficient mice displayed delayed chondrogenesis during the early phase of fracture healing as well as significantly decreased flexural rigidity and moment of inertia of the fracture callus 21 days after fracture. Mdk-deficiency diminished beta-catenin expression in chondrocytes and delayed presence of macrophages during early fracture healing. We also investigated the impact of Mdk knockdown using siRNA on ATDC5 chondroprogenitor cells in vitro. Knockdown of Mdk expression resulted in a decrease of beta-catenin and chondrogenic differentiation-related matrix proteins, suggesting that delayed chondrogenesis during fracture healing in Mdk-deficient mice may be due to a cell-autonomous mechanism involving reduced beta-catenin signaling. Our results demonstrated that Mdk plays a crucial role in the early inflammation phase and during the development of cartilaginous callus in the fracture healing process.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281158/
_version_	1613172299203084288

Midkine-Deficiency Delays Chondrogenesis during the Early Phase of Fracture Healing in Mice

Similar Items