Department of Spinal Surgery, People's Hospital of Longhua Shenzhen, Shenzhen, China; School of Life Sciences, Northwestern Polytechnical University, Xi'an, China; Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, China.
School of Life Sciences, Northwestern Polytechnical University, Xi'an, China; Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, China.
Bone. 2020 Jan;130:115108. doi: 10.1016/j.bone.2019.115108. Epub 2019 Nov 5.
Bone loss has been supposed to be the greatest damage to the health of astronauts. It is generally believed that the mechanical unloading induced by microgravity is the main cause of bone loss. However, besides mechanical unloading, many evidences from animal models and spaceflight missions indicate that microgravity conditions can cause some stress reactions and elevated endogenous glucocorticoid (GC) levels. High levels of GCs can lead to bone loss. This study aimed to investigate whether elevated GC levels are involved in hindlimb unloading (HLU)-induced bone loss in mice. Col2.3-11β-hydroxysteroid dehydrogenase type 2 (Col2.3-11β-HSD2) transgenic mice which are characterized by specific blocking GC signaling in mature osteoblasts and osteocytes were used. Male 14-week-old Col2.3-11β-HSD2 transgenic mice and wild type littermates were tail-suspended or kept under ambulatory conditions. At the endpoint, the tibias were examined by micro-computed tomography and histomorphometry, and bone turnover was analyzed by serum biochemistry, histochemistry staining, immunohistochemistry, and real-time PCR. Mice exposed to unloading occurred a significant increase in serum GC concentrations. Compared with non-unloaded controls, HLU led to a severe damage in cortical bone microstructure and bone strength of the tibia in wild type mice but not transgenic littermates. Osteoblast activity and bone formation were inhibited, whereas osteoclast activity and bone resorption were promoted in the tibial cortical bone of wild type mice following HLU, features absented in transgenic mice. Furthermore, HLU resulted in a significant increase in the number of sclerostin-producing and receptor activator of nuclear factor-κ B ligand (RANKL)-positive osteocytes, and apoptotic osteoblasts and osteocytes in wild type mice of unloading but not in unloaded transgenic mice. In conclusion, cortical bone loss during HLU is mediated through enhancing GC signaling in osteoblasts and osteocytes and subsequently restraining bone formation and activating bone resorption. It suggests that elevated GC levels play an important role in cortical bone loss in response to mechanical unloading.
骨丢失被认为是对宇航员健康的最大危害。普遍认为，微重力引起的机械卸载是导致骨丢失的主要原因。然而，除了机械卸载，来自动物模型和太空飞行任务的许多证据表明，微重力条件会引起一些应激反应和内源性糖皮质激素（GC）水平升高。高水平的 GCs 可导致骨丢失。本研究旨在探讨 GC 水平升高是否参与了小鼠后肢去负荷（HLU）诱导的骨丢失。使用 Col2.3-11β-羟类固醇脱氢酶 2（Col2.3-11β-HSD2）转基因小鼠，该小鼠的特点是在成熟成骨细胞和破骨细胞中特异性阻断 GC 信号。14 周龄雄性 Col2.3-11β-HSD2 转基因小鼠和野生型同窝仔鼠进行尾部悬吊或自由活动。在实验终点，通过 micro-CT 和组织形态计量学检查胫骨，通过血清生化、组织化学染色、免疫组织化学和实时 PCR 分析骨转换。去负荷暴露的小鼠血清 GC 浓度显著升高。与非去负荷对照相比，HLU 导致野生型小鼠胫骨皮质骨微观结构和骨强度严重受损，但转基因同窝仔鼠未受损。HLU 后，野生型小鼠胫骨皮质骨中成骨细胞活性和骨形成受到抑制，而破骨细胞活性和骨吸收受到促进，而转基因小鼠则无此特征。此外，HLU 导致产生骨硬化蛋白的和核因子-κ B 配体（RANKL）阳性破骨细胞的数量显著增加，以及野生型去负荷小鼠的凋亡成骨细胞和破骨细胞，但未在非去负荷转基因小鼠中观察到这些现象。总之，HLU 期间皮质骨丢失是通过增强成骨细胞和破骨细胞中的 GC 信号转导来介导的，随后抑制骨形成并激活骨吸收。这表明，GC 水平升高在机械卸载引起的皮质骨丢失中起重要作用。
