| 8 | 0 | 13 |
| 下载次数 | 被引频次 | 阅读次数 |
失重性骨骼系统退化是长期力学卸载和微重力环境下常见的健康问题，严重影响航天员的身体状况。冬眠动物，如达乌尔黄鼠，能够通过调控离子稳态、Wnt/β-联蛋白信号通路、NF-κB受体激活蛋白配体信号及骨形成与骨吸收等多种机制，有效防止骨质流失。这些机制为太空失重性骨质疏松抵抗药物及康复策略的开发提供了宝贵的启示。本文通过比较冬眠和失重模型在废用力学条件下的分子响应，揭示了二者在骨骼稳态维持中的异同，为人类应对失重、衰老及慢性骨骼疾病提供了新的思路。未来的研究有望推动冬眠技术在航天医学中的应用，并为防治人类多种疾病提供创新性视角和策略。
Abstract：Weightlessness-induced skeletal degeneration is a major health challenge associated with prolonged mechanical unloading and microgravity, severely affecting astronauts' physical well-being. Hibernating animals, such as the Daurian ground squirrel(Spermophilus dauricus), are able to avert bone loss by modulating ion homeostasis, the Wnt/β-catenin pathway, RANKL signaling, and the dynamic balance between bone formation and resorption. These mechanisms provide valuable insights for developing pharmacological interventions and rehabilitation strategies targeting spaceflight-related osteoporosis. By comparing the molecular responses of hibernation and unloading models under conditions of disuse, this study uncovers both convergent and divergent features in the maintenance of skeletal homeostasis, thereby providing new perspectives for addressing weightlessness, aging, and chronic bone diseases in humans. Future research may further advance the application of hibernation-based technologies in space medicine and inspire innovative approaches to the prevention and treatment of a broad range of human diseases.
[1]VICO L, COLLET P, GUIGNANDON A, et al. Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts[J]. Lancet, 2000, 355(9215):1607-1611.DOI:10.1016/S0140-6736(00)02217-0.
[2]SUN L, MIYAJI N, YANG M, et al. Astaxanthin prevents atrophy in slow muscle fibers by inhibiting mitochondrial reactive oxygen species via a mitochondria-mediated apoptosis pathway[J]. Nutrients, 2021,13(2):379. DOI:10.3390/nu13020379.
[3]NUNES EA, STOKES T, MCKENDRY J, et al. Disuse-induced skeletal muscle atrophy in disease and nondisease states in humans:mechanisms, prevention, and recovery strategies[J]. Am J Physiol Cell Physiol, 2022, 322(6):C1068-C1084. DOI:10.1152/ajpcell.00425.2021.
[4]SMITH SM, HEER M, SHACKELFORD LC, et al. Bone metabolism and renal stone risk during International Space Station missions[J].Bone, 2015, 81:712-720. DOI:10.1016/j.bone.2015.10.002.
[5]邢昕,付有涛,刘新宇,等.达乌尔黄鼠的资源利用及模式动物化研究进展[J].中国实验动物学报, 2024, 32(8):1052-1058. DOI:10.3969/j.issn.1005-4847.2024.08.012.
[6]党凯,高云芳.冬眠动物骨骼肌生理适应及机制的研究进展[J].动物学杂志, 2016, 51(3):497-506. DOI:10.13859/j.cjz.201603018.
[7]白亚楠,万美玉,狄晓可,等.淫羊藿苷对尾悬吊模拟失重诱导大鼠骨丢失的防护作用[J].中成药, 2023, 45(9):2890-2895.
[8]HOLLANDER J, GORE M, FIEBIG R, et al. Spaceflight downregulates antioxidant defense systems in rat liver[J]. Free Radic Biol Med,1998, 24(2):385-390. DOI:10.1016/s0891-5849(97)00278-5.
[9]ARFAT Y, RANI A, JINGPING W, et al. Calcium homeostasis during hibernation and in mechanical environments disrupting calcium homeostasis[J]. J Comp Physiol B, 2020, 190(1):1-16. DOI:10.1007/s00360-019-01255-3.
[10]WHEDON GD, LUTWAK L, RAMBAUT P, et al. Effect of weightlessness on mineral metabolism; metabolic studies on Skylab orbital space flights[J]. Calcif Tissue Res, 1976, 21 Suppl:423-430.
[11]RAMBAUT PC, JOHNSTON RS. Prolonged weightlessness and calcium loss in man[J]. Acta Astronaut, 1979, 6(9):1113-1122. DOI:10.1016/0094-5765(79)90059-6.
[12]MORGAN JL, ZWART SR, HEER M, et al. Bone metabolism and nutritional status during 30-day head-down-tilt bed rest[J]. J Appl Physiol(1985), 2012, 113(10):1519-1529. DOI:10.1152/japplphysiol.01064.2012.
[13]SUTOR TW, KURA J, MATTINGLY AJ, et al. The effects of exercise and activity-based physical therapy on bone after spinal cord injury[J].Int J Mol Sci, 2022, 23(2):608. DOI:10.3390/ijms23020608.
[14]SMITH SM, WASTNEY ME, O'BRIEN KO, et al. Bone markers,calcium metabolism, and calcium kinetics during extended-duration space flight on the mir space station[J]. J Bone Miner Res, 2005,20(2):208-218. DOI:10.1359/JBMR.041105.
[15]LANG TF, LEBLANC AD, EVANS HJ, et al. Adaptation of the proximal femur to skeletal reloading after long-duration spaceflight[J]. J Bone Miner Res, 2006, 21(8):1224-1230. DOI:10.1359/jbmr.060509.
[16]KANEPS AJ, STOVER SM, LANE NE. Changes in canine cortical and cancellous bone mechanical properties following immobilization and remobilization with exercise[J]. Bone, 1997, 21(5):419-423.DOI:10.1016/s8756-3282(97)00167-1.
[17]VICO L, BOURRIN S, GENTY C, et al. Histomorphometric analyses of cancellous bone from COSMOS 2044 rats[J]. J Appl Physiol(1985),1993, 75(5):2203-2208. DOI:10.1152/jappl.1993.75.5.2203.
[18]GLOBUS RK, MOREY-HOLTON E. Hindlimb unloading:rodent analog for microgravity[J]. J Appl Physiol(1985), 2016, 120(10):1196-1206. DOI:10.1152/japplphysiol.00997.2015.
[19]GARG P, STRIGINI M, PEURIèRE L, et al. The skeletal cellular and molecular underpinning of the murine hindlimb unloading model[J].Front Physiol, 2021, 12:749464. DOI:10.3389/fphys.2021.749464.
[20]GERBAIX M, GNYUBKIN V, FARLAY D, et al. One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties,osteocyte survival and lacunae volume in mature mice skeletons[J].Sci Rep, 2017, 7(1):2659. DOI:10.1038/s41598-017-03014-2.
[21]GAO X, WANG S, ZHANG J, et al. Differential bone remodeling mechanism in hindlimb unloaded rats and hibernating Daurian ground squirrels:a comparison between artificial and natural disuse[J]. J Comp Physiol B, 2021, 191(4):793-814. DOI:10.1007/s00360-021-01375-9.
[22]SMITH SM, ABRAMS SA, DAVIS-STREET JE, et al. Fifty years of human space travel:implications for bone and calcium research[J]. Annu Rev Nutr, 2014, 34:377-400. DOI:10.1146/annurev-nutr-071813-105440.
[23]LEBLANC AD, SCHNEIDER VS, EVANS HJ, et al. Bone mineral loss and recovery after 17 weeks of bed rest[J]. J Bone Miner Res,1990, 5(8):843-850. DOI:10.1002/jbmr.5650050807.
[24]崔伟,史之祯，付宏伟,等.两种骨丢失动物模型骨质、甲状旁腺激素和降钙素的变化比较[J].中国应用生理学杂志, 1997(1):6-9.
[25]李煜,张新昌,朱雷,等.小鼠尾悬吊法模拟微重力对骨代谢的影响[J].武警医学, 2016, 27(4):366-369. DOI:10.3969/j.issn.1004-3594.2016.04.013.
[26]韩相伟.跳跃训练对模拟失重大鼠骨密度和骨代谢指标的影响[J].山东体育学院学报, 2013, 29(4):55-60. DOI:10.3969/j.issn.1006-2076.2013.04.012.
[27]KIMURA Y, NAKAI Y, INO Y, et al. Identification of gravity-responsive serum proteins in spaceflight mice using a quantitative proteomic approach with data-independent acquisition mass spectrometry[J].Proteomics, 2024, 24(9):e2300214. DOI:10.1002/pmic.202300214.
[28]XIN M, YANG Y, ZHANG D, et al. Attenuation of hind-limb suspension-induced bone loss by curcumin is associated with reduced oxidative stress and increased vitamin D receptor expression[J].Osteoporos Int, 2015, 26(11):2665-2676. DOI:10.1007/s00198-015-3153-7.
[29]ZHAO Y, WANG HL, LI TT, et al. Baicalin ameliorates dexamethasone-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway[J]. Drug Des Devel Ther, 2020, 14:195-206. DOI:10.2147/DDDT.S225516.
[30]CHEN M, HU X, WU M, et al. Serum levels of OPG, RANKL, and RANKL/OPG ratio in patients with ankylosing spondylitis:a systematic review and meta-analysis[J]. Immunol Invest, 2019, 48(5):490-504.DOI:10.1080/08820139.2019.1567531.
[31]杨先炯,毛新建,罗庆,等. Wnt3a/β-catenin信号通路调节模拟微重力诱导的骨髓间充质干细胞增殖抑制[J].空间科学学报, 2016,36(1):63-69. DOI:10.11728/cjss2016.01.063.
[32]梁萌,杨肖,樊瑜波,等.模拟微重力效应对骨细胞Wnt/β-catenin通路的影响[J].航天医学与医学工程, 2014, 27(3):164-167.DOI:10.16289/j.cnki.1002-0837.2014.03.009.
[33]WANG L, YOU X, LOTINUN S, et al. Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk[J]. Nat Commun, 2020, 11(1):282. DOI:10.1038/s41467-019-14146-6.
[34]HU Y, TIAN H, CHEN W, et al. The critical role of the Piezo1/β-catenin/ATF4 axis on the stemness of Gli1(+)BMSCs during simulated microgravity-induced bone loss[J].Adv Sci(Weinh), 2023, 10(32):e2303375. DOI:10.1002/advs.202303375.
[35]LIU C, GAO X, LI Y, et al. The mechanosensitive lncRNA Neat1promotes osteoblast function through paraspeckle-dependent Smurf1mRNA retention[J]. Bone Res, 2022, 10(1):18. DOI:10.1038/s41413-022-00191-3.
[36]JIANG S, LI H, ZHANG L, et al. Generic Diagramming Platform(GDP):a comprehensive database of high-quality biomedical graphics[J]. Nucleic Acids Res, 2025, 53(D1):D1670-D1676. DOI:10.1093/nar/gkae973.
[37]MCGEE ME, MAKI AJ, JOHNSON SE, et al. Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse(hibernation)in grizzly bears(Ursus arctos horribilis)[J]. Bone, 2008, 42(2):396-404. DOI:10.1016/j.bone.2007.10.010.
[38]FEDOROV VB, GOROPASHNAYA AV, TøIENØ, et al. Preservation of bone mass and structure in hibernating black bears(Ursus americanus)through elevated expression of anabolic genes[J].Funct Integr Genomics, 2012, 12(2):357-365. DOI:10.1007/s10142-012-0266-3.
[39]GOROPASHNAYA AV, TØIENØ, RAMARAJ T, et al. Transcriptional changes and preservation of bone mass in hibernating black bears[J].Sci Rep, 2021, 11(1):8281. DOI:10.1038/s41598-021-87785-9.
[40]MCGEE-LAWRENCE M, BUCKENDAHL P, CARPENTER C, et al. Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation[J]. J Exp Biol, 2015, 218(Pt 13):2067-2074.DOI:10.1242/jeb.120725.
[41]DONAHUE SW, VAUGHAN MR, DEMERS LM, et al. Serum markers of bone metabolism show bone loss in hibernating bears[J]. Clin Orthop Relat Res, 2003,(408):295-301. DOI:10.1097/01.blo.0000129556.26221.c0.
[42]GUSTAFSON AW, BELT WD. The adrenal cortex during activity and hibernation in the male little brown bat, Myotis lucifugus lucifugus:annual rhythm of plasma cortisol levels[J]. Gen Comp Endocrinol,1981, 44(3):269-278. DOI:10.1016/0016-6480(81)90001-0.
[43]DONAHUE SW, GALLEY SA, VAUGHAN MR, et al. Parathyroid hormone may maintain bone formation in hibernating black bears(Ursus americanus)to prevent disuse osteoporosis[J]. J Exp Biol,2006, 209(Pt 9):1630-1638. DOI:10.1242/jeb.02185.
[44]VESTERGAARD P, STØEN OG, SWENSON JE, et al. Vitamin D status and bone and connective tissue turnover in brown bears(Ursus arctos)during hibernation and the active state[J]. PloS one, 2011,6(6):e21483. DOI:10.1371/journal.pone.0021483.
[45]HE Y, KONG Y, YIN R, et al. Remarkable plasticity of bone iron homeostasis in hibernating daurian ground squirrels(spermophilus dauricus)may be involved in bone maintenance[J]. Int J Mol Sci,2022, 23(24):15858. DOI:10.3390/ijms232415858.
[46]YIN R, ZHANG J, XU S, et al. Resistance to disuse-induced iron overload in Daurian ground squirrels(Spermophilus dauricus)during extended hibernation inactivity[J]Comp Biochem Physiol B Biochem Mol Biol, 2022, 257:110650. DOI:10.1016/j.cbpb.2021.110650.
[47]ZHANG J, WANG H, YANG H, et al. IGF-1 and myostatin-mediated co-regulation in skeletal muscle and bone of Daurian ground squirrels(Spermophilus dauricus)during different hibernation stages[J]. Comp Biochem Physiol A Mol Integr Physiol, 2024, 297:111716. DOI:10.1016/j.cbpa.2024.111716.
[48]GAO X, WANG S, SHEN S, et al. Differential bone remodeling mechanism in hindlimb unloaded and hibernating Daurian ground squirrels:a comparison between artificial and natural disuse within the same species[J]. J Comp Physiol B, 2023, 193(3):329-350.DOI:10.1007/s00360-023-01482-9.
[49]吕铮,宋士一,杨明,等.达乌尔黄鼠入眠准备期的体温、代谢率及能量特征[J].兽类学报, 2014, 34(4):348-355.
[50]杨明,邢昕,管淑君,等.达乌尔黄鼠冬眠期间体温的变化和冬眠模式[J].兽类学报, 2011, 31(4):387-395.
[51]ZHANG J, CHANG H, YIN R, et al. A temporal study on musculoskeletal morphology and metabolism in hibernating Daurian ground squirrels(Spermophilus dauricus)[J]. Bone, 2021, 144:115826. DOI:10.1016/j.bone.2020.115826.
[52]REN Y, SONG S, LIU X, et al. Phenotypic changes in the metabolic profile and adiponectin activity during seasonal fattening and hibernation in female Daurian ground squirrels(Spermophilus dauricus)[J].Integr Zool, 2022, 17(2):297-310. DOI:10.1111/1749-4877.12504.
[53]FERRON M, WEI J, YOSHIZAWA T, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism[J]. Cell,2010, 142(2):296-308. DOI:10.1016/j.cell.2010.06.003.
[54]王建锋,杜海荣,张明海.亚洲黑熊冬眠前后生理生化差异[J].野生动物学报, 2022, 43(1):58-63. DOI:10.3969/j.issn.1000-0127.2022.01.009.
[55]BAUMAN WA, MERYN S, FLORANT GL. Pancreatic hormones in the nonhibernating and hibernating golden mantled ground squirrel[J].Comp Biochem Physiol A Comp Physiol, 1987, 86(2):241-244. DOI:10.1016/0300-9629(87)90324-0.
[56]FLORANT GL, PORST H, PEIFFER A, et al. Fat-cell mass, serum leptin and adiponectin changes during weight gain and loss in yellow-bellied marmots(Marmota flaviventris)[J]. J Comp Physiol B,2004, 174(8):633-639. DOI:10.1007/s00360-004-0454-0.
[57]SEGER RL, CROSS RA, ROSEN CJ, et al. Investigating the mechanism for maintaining eucalcemia despite immobility and anuria in the hibernating American black bear(Ursus americanus)[J]. Bone, 2011,49(6):1205-1212. DOI:10.1016/j.bone.2011.08.017.
[58]DOHERTY AH, FLORANT GL, DONAHUE SW. Endocrine regulation of bone and energy metabolism in hibernating mammals[J].IIntegr Comp Biol, 2014, 54(3):463-483. DOI:10.1093/icb/icu001.
[59]刘盈,周满如,黎卓熹,等. Denosumab治疗类风湿性关节炎的研究现状[J].中国临床药理学杂志, 2021, 37(8):1012-1015.DOI:10.13699/j.cnki.1001-6821.2021.08.021.
[60]谢忠建.从OPG-RANKL-RANK通路到骨质疏松症分子靶向治疗[J].中华骨质疏松和骨矿盐疾病杂志, 2022, 15(2):126-134. DOI:10.3969/j.issn.1674-2591.2022.02.002.
[61]李昊.周期性动态力学载荷对抗骨质疏松的研究[D].北京:中国人民解放军军事科学院军事医学研究院, 2013.
[62]吴大蔚,徐冲,李志利,等.中国空间站任务航天医学研究进展与展望[J].载人航天, 2025, 31(2):143-154. DOI:10.3969/j.issn.1674-5825.2025.02.001.
基本信息:
DOI：10.16289/j.cnki.1002-0837.2026.03017
中图分类号:R852
引用信息:
[1]刘煜雯,张根洋,党凯,等.冬眠与失重条件下骨骼响应的比较：对抗太空骨质流失的启示[J].航天医学与医学工程,2026,37(03):329-336.DOI:10.16289/j.cnki.1002-0837.2026.03017.
基金信息:
国家自然科学基金（32371371）; 中国载人航天工程空间站应用与发展工程-空间科学与应用项目（KJZ-YY-NSM0613）; 广东省基础与应用基础研究基金（2024A1515013078）; 中国博士后科学基金（2025M774370）; 西北工业大学博士学位论文创新基金（CX2024084）;西北工业大学本科生创新创业训练计划（XN2024227）
2026-06-25
2026-06-25