Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice
Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice
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DOI：
10.3390/ijms21072547
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Kaji, Hiroshi
中科院分区：
文献类型：
--
作者：
Kawao, Naoyuki;Morita, Hironobu;Kaji, Hiroshi
机械性去负荷同时引起肌肉和骨的丢失，但其机制尚未完全清楚。骨骼肌和骨骼之间的相互作用最近已经注意到。尽管经典的无翅相关整合位点（Wnt）/β-连环蛋白信号传导对骨代谢至关重要，但其在肌肉和骨相互作用中的作用仍然未知。在这里，我们进行了全面的DNA微阵列分析，以澄清体液因素连接肌肉骨骼的机械卸载和超重与3 g的小鼠。我们确定Dickkopf（Dkk）2，Wnt/β-连环蛋白信号传导抑制剂，作为一个基因，其表达增加后肢卸载（HU）和减少超重力在小鼠比目鱼肌。HU显著升高小鼠血清Dkk 2水平和比目鱼肌中Dkk 2 mRNA水平，而超重显著降低这些Dkk 2水平。在简单回归分析中，血清Dkk 2水平分别与小鼠胫骨骨小梁密度和核因子-κ B配体受体激活剂（RANKL）mRNA水平呈负相关和正相关。此外，切应力显着抑制Dkk 2 mRNA在C2 C12细胞中的表达，和环氧合酶抑制剂显着拮抗剪切应力对Dkk 2表达的影响。另一方面，Dkk 2抑制成骨基因、碱性磷酸酶活性和矿化的mRNA水平，并增加小鼠成骨细胞中RANKL mRNA水平。总之，我们发现，肌肉和血清Dkk 2水平的积极和消极调节在机械卸载和超重小鼠，分别。骨骼肌中Dkk 2表达的增加可能有助于废用和微重力诱导的骨和肌肉损失。
Mechanical unloading simultaneously induces muscle and bone loss, but its mechanisms are not fully understood. The interactions between skeletal muscle and bone have been recently noted. Although canonical wingless-related integration site (Wnt)/beta-catenin signaling is crucial for bone metabolism, its roles in the muscle and bone interactions have remained unknown. Here, we performed comprehensive DNA microarray analyses to clarify humoral factors linking muscle to bone in response to mechanical unloading and hypergravity with 3 g in mice. We identified Dickkopf (Dkk) 2, a Wnt/beta-catenin signaling inhibitor, as a gene whose expression was increased by hindlimb unloading (HU) and reduced by hypergravity in the soleus muscle of mice. HU significantly elevated serum Dkk2 levels and Dkk2 mRNA levels in the soleus muscle of mice whereas hypergravity significantly decreased those Dkk2 levels. In the simple regression analyses, serum Dkk2 levels were negatively and positively related to trabecular bone mineral density and mRNA levels of receptor activator of nuclear factor-kappa B ligand (RANKL) in the tibia of mice, respectively. Moreover, shear stress significantly suppressed Dkk2 mRNA levels in C2C12 cells, and cyclooxygenase inhibitors significantly antagonized the effects of shear stress on Dkk2 expression. On the other hand, Dkk2 suppressed the mRNA levels of osteogenic genes, alkaline phosphatase activity and mineralization, and it increased RANKL mRNA levels in mouse osteoblasts. In conclusion, we showed that muscle and serum Dkk2 levels are positively and negatively regulated during mechanical unloading and hypergravity in mice, respectively. An increase in Dkk2 expression in the skeletal muscle might contribute to disuse- and microgravity-induced bone and muscle loss.