MOE Key Lab of Bioinformatics, Department of Biological Science and Biotechnology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
State Key Laboratory of Automotive Safety and Energy, Tsinghua University, Beijing 100084, China.
Biomaterials. 2014 Sep;35(28):8273-83. doi: 10.1016/j.biomaterials.2014.06.020. Epub 2014 Jun 26.
Skeletons have significant bone loss (osteoporosis) under microgravity environment. This study showed that microbial polyhydroxyalkanoates (PHA) degradation product, and also ketone body 3-hydroxybutyrate acid (3HB) and its derivative 3-hydroxybutyrate methyl ester (3HBME) inhibit the development of osteoporosis in mice maintained under simulated microgravity, helping preserve bone microstructure and mechanical property. Mice orally administrated with 3HB or 3HBME recovered much more quickly from osteoporosis resulted from simulated microgravity compared with the controls without 3HB or 3HBME treatments due to less calcium loss to the sera. It was known that abnormal activation of osteoclasts induced by microgravity led to bone tissue absorption and thus osteoporosis. In this study, it was found that 3HB or 3HBME down-regulated the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the transcription factor of pre-osteoclast differentiation. When NFATc1 activation and downstream functions were inhibited, 3HB or 3HBME was able to strongly reduce pre-osteoclast differentiation. As a result, bone absorption was prevented. It was demonstrated that 100 mg/kg 3HB resulted in the most obvious effect on osteoporosis prevention. Based on these results, 3HB and 3HBME should be further developed as novel drug candidates against osteoporosis induced by microgravity.
在微重力环境下，骨骼会出现明显的骨质流失（骨质疏松症）。本研究表明，微生物聚羟基脂肪酸酯（PHA）降解产物，以及酮体 3-羟基丁酸（3HB）及其衍生物 3-羟基丁酸甲酯（3HBME），可抑制模拟微重力环境下维持的小鼠骨质疏松症的发展，有助于保持骨微观结构和机械性能。与未用 3HB 或 3HBME 治疗的对照组相比，经口给予 3HB 或 3HBME 的小鼠从模拟微重力引起的骨质疏松症中恢复得更快，因为血清中钙的流失较少。众所周知，微重力引起的破骨细胞异常激活导致骨组织吸收，从而导致骨质疏松症。在这项研究中，发现 3HB 或 3HBME 下调核因子活化 T 细胞细胞质 1（NFATc1），NFATc1 是破骨前细胞分化的转录因子。当 NFATc1 的激活和下游功能受到抑制时，3HB 或 3HBME 能够强烈抑制破骨前细胞的分化。因此，防止了骨吸收。结果表明，100mg/kg 的 3HB 对预防骨质疏松症的效果最为明显。基于这些结果，3HB 和 3HBME 应进一步开发为针对微重力引起的骨质疏松症的新型药物候选物。
