Role and mechanism of dexmedetomidine in regulating bone metabolism in tail-suspended osteoporotic rats

GUO Yunliang; WANG Can; ZHANG Xinyu; YAN Zedong; WEN Zhipeng; LIU Ruobing; LIU Pengsen

doi:10.16016/j.2097-0927.202408018

您当前的位置：

首页 >

文章列表页 >

Role and mechanism of dexmedetomidine in regulating bone metabolism in tail-suspended osteoporotic rats

Basic Medicine | 更新时间：2025-02-26

- Role and mechanism of dexmedetomidine in regulating bone metabolism in tail-suspended osteoporotic rats
- Journal of Army Medical University Vol. 47, Issue 3, Pages: 226-233(2025)
- 作者机构：
  
  1.河南省中医院麻醉科，河南郑州
  2.空军军医大学军事生物医学工程学系，陕西西安
- 作者简介：
  
  LIU Pengsen， E-mail： 283786269@qq.com.
- 基金信息：
  
  the National Natural Science Foundation for Young Scholars of China(12302412);the General Program of National Natural Science Foundation of China(52377229)
- DOI：10.16016/j.2097-0927.202408018
  CLC： R322.71;R681.02;R971.3
- Received：06 August 2024，
  
  Revised：01 November 2024，
  
  Published：15 February 2025
- 稿件说明：
移动端阅览
‍郭云亮，王灿，张新雨，等.右美托咪定对于尾吊骨质疏松大鼠骨代谢调控作用及机制［J］.陆军军医大学学报，2025，47（03）：226-233.DOI：10.16016/j.2097-0927.202408018.

GUO Y L，WANG C，ZHANG X Y，et al.Role and mechanism of dexmedetomidine in regulating bone metabolism in tail-suspended osteoporotic rats［J］.J Army Med Univ，2025，47（03）：226-233.DOI：10.16016/j.2097-0927.202408018.
‍郭云亮，王灿，张新雨，等.右美托咪定对于尾吊骨质疏松大鼠骨代谢调控作用及机制［J］.陆军军医大学学报，2025，47（03）：226-233.DOI：10.16016/j.2097-0927.202408018. DOI：

GUO Y L，WANG C，ZHANG X Y，et al.Role and mechanism of dexmedetomidine in regulating bone metabolism in tail-suspended osteoporotic rats［J］.J Army Med Univ，2025，47（03）：226-233.DOI：10.16016/j.2097-0927.202408018. DOI：

摘要

‍

目的

研究右美托咪定（dexmedetomidine， DEX）对于尾吊大鼠骨丢失的作用效果，并初步探究其对于骨代谢的调控机制。

方法

30只雄性大鼠按照随机数字表法分为对照（Control）组、尾吊（HU）组、尾吊+右美托咪定（HU+DEX）组，每组10只。HU组和HU+DEX组大鼠行4周后肢悬吊处理，HU+DEX组大鼠从尾吊当天开始进行DEX干预（10 μg/kg，隔天1次），Control组和HU组大鼠每日行等量生理盐水注射。通过骨组织学染色检测小梁骨面积占比，通过生物力学三点弯曲测试检测最大载荷、刚度及断裂能，通过钙黄绿素/茜素红荧光双标检测矿化沉积率和骨形成速率，通过抗酒石酸酸性磷酸酶（tartrate-resistant

acid phosphatase， TRAP）染色分析骨表面破骨细胞数。分离尾吊大鼠胫骨原代成骨细胞，进行DEX干预（1 nmol/L），通过碱性磷酸酶染色和活性测试检测碱性磷酸酶阳性成骨细胞占比和成骨细胞碱性磷酸酶活性，通过成骨相关基因表达检测成骨活性功能相关因子，包括骨钙素（osteocalcin，

Ocn

）、Runt相关转录因子2（runt related transcription factor 2，

Runx2

）、Osterix蛋白（osterix，

Osx

）和I型胶原蛋白（type 1 collagen，

Col1

）。

结果

动物实验结果揭示，DEX显著增加了尾吊大鼠胫骨骨小梁的面积占比（

0.001），显著抑制尾吊大鼠骨力学强度的降低（

0.001），显著增加尾吊大鼠小梁骨矿化沉积率和新骨形成速率（

0.001）。体外细胞实验结果表明，DEX显著增加了尾吊大鼠体外原代成骨细胞碱性磷酸酶活性及碱性磷酸酶阳性成骨细胞数量（

0.01），并上调了成骨分化相关基因（

Ocn

、

Runx2

、

Osx

、

Col1

）的表达水平（

0.01）。

结论

DEX能对抗尾吊大鼠骨丢失，刺激成骨细胞的骨形成可能是其作用机制。

Abstract

‍Objective‍

‍To investigate the effect of dexmedetomidine （Dex） on bone loss in tail-suspended rats and primarily explore its regulatory mechanism on bone metabolism.

Methods

‍A total of 30 male rats were randomly divided into a control group， a model group， and a Dex group， with 10 animals in each group. Rat model of osteoporosis was established by hind limb suspension for 4 weeks. Dex at a dose of 10 μg/kg was given intraperitoneally， once every other day from the day of tail suspension. And equal amount of normal saline was given to the control and model group. Bone histological staining was used to observe the trabecular bone area fraction. Biomechanical three-point bending test was employed to measure the maximum load， stiffness， and fracture energy. Dual calcein/alizarin red fluorescence labeling and tartrate resistant acid phosphatase （TRAP） staining were applied respectively to detect the mineral apposition rate and bone formation rate as well as the number of osteoclasts on bone surfaces. Secondly， after primary osteoblasts were isolated from the tibiae of tail-suspended rats and then treated with 1 nmol/L Dex， the proportion of alkaline phosphatase （ALP）-positive osteoblasts and the activity of the enzyme were detected by ALP staining and activity test. qRT-PCR was applied to measure the expression of osteogenic activity-related factors， including osteocalcin （Ocn）， Runt related transcription factor 2 （Runx2）， Osterix protein （Osx）， and type 1 collagen （Col1）.

Results

‍The animal experiments revealed that Dex treatment significantly increased the tibial trabecular bone area fraction， inhibited the decrease in bone mechanical strength， and enhanced the mineralization deposition rate and new bone formation rate of trabecular bone in the tail-suspended rats （all P<0.001）. The in vitro experiments showed that Dex treatment obviously improved ALP activity and the number of ALP-positive osteoblasts in primary osteoblasts isolated from tail-suspended rats （P<0.01）， and up-regulated the expression levels of osteogenic differentiation-related genes， such as Ocn， Runx2， Osx and Col1 （P<0.01）.

Conclusion

‍Dex exerts anti-bone loss effect in tail-suspended rats， which may be associated with its stimulation on osteoblast-mediated bone formation.

关键词

Keywords

references

AIBAR-ALMAZÁN A ， VOLTES-MARTÍNEZ A ， CASTELLOTE-CABALLERO Y ， et al . Current status of the diagnosis and management of osteoporosis ［J］. Int J Mol Sci ， 2022 ， 23 （ 16 ）： 9465 . DOI： 10.3390/ijms23169465 http://dx.doi.org/10.3390/ijms23169465 .

ROLVIEN T ， AMLING M . Disuse osteoporosis： clinical and mechanistic insights ［J］. Calcif Tissue Int ， 2022 ， 110 （ 5 ）： 592 - 604 . DOI： 10.1007/s00223-021-00836-1 http://dx.doi.org/10.1007/s00223-021-00836-1 .

BUETTMANN E G ， GOLDSCHEITTER G M ， HOPPOCK G A ， et al . Similarities between disuse and age-induced bone loss ［J］. J Bone Miner Res ， 2022 ， 37 （ 8 ）： 1417 - 1434 . DOI： 10.1002/jbmr.4643 http://dx.doi.org/10.1002/jbmr.4643 .

LIU X T ， LI Y Q ， KANG L ， et al . Recent advances in the clinical value and potential of dexmedetomidine ［J］. J Inflamm Res ， 2021 ， 14 ： 7507 - 7527 . DOI： 10.2147/JIR.S346089 http://dx.doi.org/10.2147/JIR.S346089 .

TASBIHGOU S R ， BARENDS C R M ， ABSALOM A R . The role of dexmedetomidine in neurosurgery ［J］. Best Pract Res Clin Anaesthesiol ， 2021 ， 35 （ 2 ）： 221 - 229 . DOI： 10.1016/j.bpa.2020.10.002 http://dx.doi.org/10.1016/j.bpa.2020.10.002 .

MAHMOUD M ， BARBI E ， MASON K P . Dexmedetomidine： what’s new for pediatrics？ A narrative review ［J］. J Clin Med ， 2020 ， 9 （ 9 ）： 2724 . DOI： 10.3390/jcm9092724 http://dx.doi.org/10.3390/jcm9092724 .

CARNET LE PROVOST K ， KEPP O ， KROEMER G ， et al . Trial watch： dexmedetomidine in cancer therapy ［J］. Oncoimmunology ， 2024 ， 13 （ 1 ）： 2327143 . DOI： 10.1080/2162402X.2024.2327143 http://dx.doi.org/10.1080/2162402X.2024.2327143 .

TAKAHASHI K ， YOSHIKAWA Y ， KANDA M ， et al . Dexmedetomidine as a cardioprotective drug： a narrative review ［J］. J Anesth ， 2023 ， 37 （ 6 ）： 961 - 970 . DOI： 10.1007/s00540-023-03261-w http://dx.doi.org/10.1007/s00540-023-03261-w .

CHEN R ， DOU X K ， DAI M S ， et al . The role of dexmedetomidine in immune tissue and inflammatory diseases： a narrative review ［J］. Eur Rev Med Pharmacol Sci ， 2022 ， 26 （ 21 ）： 8030 - 8038 . DOI： 10.26355/eurrev_202211_30157 http://dx.doi.org/10.26355/eurrev_202211_30157 .

CHEN R ， SUN Y ， LV J ， et al . Effects of dexmedetomidine on immune cells： a narrative review ［J］. Front Pharmacol ， 2022 ， 13 ： 829951 . DOI： 10.3389/fphar.2022.829951 http://dx.doi.org/10.3389/fphar.2022.829951 .

LOU Y N ， ZOU L F ， SHEN Z Y ， et al . Protective effect of dexmedetomidine against delayed bone healing caused by morphine via PI3K/Akt mediated Nrf2 antioxidant defense system ［J］. Front Pharmacol ， 2024 ， 15 ： 1396713 . DOI： 10.3389/fphar.2024.1396713 http://dx.doi.org/10.3389/fphar.2024.1396713 .

WANG Z Y ， GE X H ， WANG Y ， et al . Mechanism of dexmedetomidine regulating osteogenesis-angiogenesis coupling through the miR-361-5p/VEGFA axis in postmenopausal osteoporosis ［J］. Life Sci ， 2021 ， 275 ： 119273 . DOI： 10.1016/j.lfs.2021.119273 http://dx.doi.org/10.1016/j.lfs.2021.119273 .

WILLIE B M ， ZIMMERMANN E A ， VITIENES I ， et al . Bone adaptation： safety factors and load predictability in shaping skeletal form ［J］. Bone ， 2020 ， 131 ： 115114 . DOI： 10.1016/j.bone.2019.115114 http://dx.doi.org/10.1016/j.bone.2019.115114 .

GALEA G L ， DELISSER P J ， MEAKIN L ， et al . Bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice ［J］. Bone ， 2020 ， 133 ： 115255 . DOI： 10.1016/j.bone.2020.115255 http://dx.doi.org/10.1016/j.bone.2020.115255 .

BRENT M B ， BRÜEL A ， THOMSEN J S . A systematic review of animal models of disuse-induced bone loss ［J］. Calcif Tissue Int ， 2021 ， 108 （ 5 ）： 561 - 575 . DOI： 10.1007/s00223-020-00799-9 http://dx.doi.org/10.1007/s00223-020-00799-9 .

DAVID V ， LAFAGE-PROUST M H ， LAROCHE N ， et al . Two-week longitudinal survey of bone architecture alteration in the hindlimb-unloaded rat model of bone loss： sex differences ［J］. Am J Physiol Endocrinol Metab ， 2006 ， 290 （ 3 ）： E440 - E447 . DOI： 10.1152/ajpendo.00293.2004 http://dx.doi.org/10.1152/ajpendo.00293.2004 .

LEVIN V A ， JIANG X ， KAGAN R . Estrogen therapy for osteoporosis in the modern era ［J］. Osteoporos Int ， 2018 ， 29 （ 5 ）： 1049 - 1055 . DOI： 10.1007/s00198-018-4414-z http://dx.doi.org/10.1007/s00198-018-4414-z .

MOUSTAFA A . Hindlimb unloading-induced reproductive suppression via downregulation of hypothalamic Kiss-1 expression in adult male rats ［J］. Reprod Biol Endocrinol ， 2021 ， 19 （ 1 ）： 37 . DOI： 10.1186/s12958-021-00694-4 http://dx.doi.org/10.1186/s12958-021-00694-4 .

BRENT M B ， BRÜEL A ， THOMSEN J S . Animal models of disuse-induced bone loss： study protocol for a systematic review ［J］. Syst Rev ， 2020 ， 9 （ 1 ）： 185 . DOI： 10.1186/s13643-020-01441-3 http://dx.doi.org/10.1186/s13643-020-01441-3 .

KIM J M ， LIN C J ， STAVRE Z ， et al . Osteoblast-osteoclast communication and bone homeostasis ［J］. Cells ， 2020 ， 9 （ 9 ）： 2073 . DOI： 10.3390/cells9092073 http://dx.doi.org/10.3390/cells9092073 .

GAO M H ， DONG C J ， CHEN Z L ， et al . Different impact of short-term and long-term hindlimb disuse on bone homeostasis ［J］. Gene ， 2024 ， 918 ： 148457 . DOI： 10.1016/j.gene. 2024.148457 http://dx.doi.org/10.1016/j.gene.2024.148457 .

LAU P ， VICO L ， RITTWEGER J . Dissociation of bone resorption and formation in spaceflight and simulated microgravity： potential role of myokines and osteokines？［J］. Biomedicines ， 2022 ， 10 （ 2 ）： 342 . DOI： 10.3390/biomedicines10020342 http://dx.doi.org/10.3390/biomedicines10020342 .

FRANCESCHI R T ， XIAO G Z . Regulation of the osteoblast-specific transcription factor， Runx2： responsiveness to multiple signal transduction pathways ［J］. J Cell Biochem ， 2003 ， 88 （ 3 ）： 446 - 454 . DOI： 10.1002/jcb.10369 http://dx.doi.org/10.1002/jcb.10369 .

GAYATRI M B ， GAJULA N N ， CHAVA S ， et al . High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis ［J］. Cell Death Discov ， 2022 ， 8 （ 1 ）： 277 . DOI： 10.1038/s41420-022-01077-3 http://dx.doi.org/10.1038/s41420-022-01077-3 .

VEGA O A ， LUCERO C M J ， ARAYA H F ， et al . Wnt/β-catenin signaling activates expression of the bone-related transcription factor RUNX2 in select human osteosarcoma cell types ［J］. J Cell Biochem ， 2017 ， 118 （ 11 ）： 3662 - 3674 . DOI： 10.1002/jcb.26011 http://dx.doi.org/10.1002/jcb.26011 .

CHANG J H ， JIN M M ， LIU J T . Dexmedetomidine pretreatment protects the heart against apoptosis in ischemia/reperfusion injury in diabetic rats by activating PI3K/Akt signaling in vivo and in vitro ［J］. Biomed Pharmacother ， 2020 ， 127 ： 110188 . DOI： 10.1016/j.biopha.2020.110188 http://dx.doi.org/10.1016/j.biopha.2020.110188 .

YANG K ， MA Y H ， XIE C M ， et al . Dexmedetomidine combined with propofol attenuates myocardial ischemia/reperfusion injury by activating the AMPK signaling pathway ［J］. Heliyon ， 2023 ， 9 （ 11 ）： e22054 . DOI： 10.1016/j.heliyon.2023.e22054 http://dx.doi.org/10.1016/j.heliyon.2023.e22054 .

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Effects of calcitonin gene-related peptide on osteogenic differentiation of human umbilical cord mesenchymal stem cells

Expression of fibroblast growth factor receptor and its role in regulating osteoblast differentiation

Effect of a novel isoflavone compound on femoral biomechanics of ovarectomied rats

Actinobacillus actinomycetemcomitans induces differentiation and gap junctional intercellular communication in cultured osteoblasts

Related Author

HE Guiqiong

XU Ling

WANG Kejian

LONG Zhimin

ZHAO Yueyang

QIU Yu

LI You

GAO Zhen

Related Institution

Department of Prosthodontics, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University

Department of Human Anatomy, Neuroscience Research Center, College of Basic Medical Sciences, Chongqing Medical University

Department of Stomatology, Second Affiliated Hospital, Army Medical University (Third Military Medical University)

Department of Medical Genetics, College of Basic Medical Sciences, Army Medical University (Third Military Medical University)

State Key Laboratory of Trauma, Burns and Combined injury, Center of Osteoporosis and Bone Development, Laboratory of Battle Injury Repair and Rehabilitation Medicine, Laboratory for Prevention and Rehabilitation of Training Injuries, Daping Hospital, Army Medical University(Third Military Medical University)

⁰