Inhibition of Midkine Augments Osteoporotic Fracture Healing.
Inhibition of Midkine Augments Osteoporotic Fracture Healing.
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DOI：
10.1371/journal.pone.0159278
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Liedert A
中科院分区：
文献类型：
--
作者：
Haffner-Luntzer M;Kemmler J;Heidler V;Prystaz K;Schinke T;Amling M;Kovtun A;Rapp AE;Ignatius A;Liedert A
肝素结合生长和分化因子中期因子（Mdk）被认为负调节成骨细胞的活性和成人骨骼中的骨形成。由于Mdk缺陷小鼠免受卵巢切除术（OVX）诱导的骨丢失，该因子也可能在绝经后骨质疏松症的发病机制中发挥作用。我们以前已经证明，Mdk在骨折愈合过程中对骨再生有负面影响。在这里，我们研究了使用Mdk抗体（Mdk-Ab）抑制Mdk是否改善了骨质疏松OVX小鼠中受损的骨愈合。使用标准化股骨截骨术模型，我们证明了Mdk血清水平在非OVX和OVX小鼠骨折后均显著增强，然而，在骨质疏松小鼠中的增加显著更大。Mdk-Ab的全身治疗通过增加骨折骨痂中的骨形成而显著改善了骨质疏松小鼠的骨愈合。在分子水平上，我们证明了Mdk-Ab处理消除了OVX诱导的骨痂中骨合成代谢β-连环蛋白信号传导的减少。此外，Mdk-Ab的注射增加了骨质疏松小鼠骨骼中的骨小梁质量。这些结果提示，拮抗Mdk可能有助于治疗骨质疏松症和骨质疏松症愈合并发症。
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.