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Abstract
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.
Highlights
The growth and differentiation factor midkine (Mdk) has been demonstrated to play an important role in bone development and remodeling [1,2,3,4]
We found no significant differences in trabecular thickness and trabecular bone volume (BV)/total volume (TV), the trabecular number was significantly increased whereas the cortical thickness was significantly decreased
There was no significant difference between both genotype groups regarding flexural rigidity, moment of inertia or bone volume to total volume fraction (BV/TV) of the fractured femur (Fig. 2B, D, F)
Summary
The growth and differentiation factor midkine (Mdk) has been demonstrated to play an important role in bone development and remodeling [1,2,3,4]. This 13 kDa heparin-binding molecule, which forms a unique growth factor family together with pleiotrophin, was originally identified to play a pivotal role in neuronal embryonic development [5]. The phenotype of Mdk-deficient mice indicated an important role of Mdk in bone development. Mdk-deficiency had an anabolic effect on cortical bone formation in response to mechanical loading in an in vivo ulna-loading model [3]. Mdk appears to be an inhibitor of osteoblast function, suggesting a negative influence of Mdk on bone remodeling
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