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2000
Volume 20, Issue 7
  • ISSN: 1574-888X
  • E-ISSN: 2212-3946

Abstract

Background

Osteoporotic fracture is a pathological fracture secondary to osteoporosis, causing disabilities and a heavy burden to the patients. In the previous study, we found that salvianolic acid B (SalB) promoted the osteogenesis of Mesenchymal Stem Cells (MSCs).

Objective

This study aimed to explore the role of SalB in osteoporotic fracture healing, as well as the potential molecular mechanism.

Methods

Human bone marrow mesenchymal stem cells (hMSCs) were treated with SalB or PBS , and an osteoporotic fracture model in Sprague-Dawley (SD) rats was established successfully. SalB or PBS was locally injected at the fracture. Eight weeks later, microCT was used to compare the healing of osteoporotic fractures with or without SalB. The relative expressions of mRNAs were measured by qRT-PCR. Bioinformatics analysis, RT-PCR, and dual luciferase reporter assay were utilized to detect the interrelation of genes. Immunohistochemistry staining was used to test expressions of proteins.

Results

In the present study, we found that SalB significantly increased the level of lncRNA- MALAT1 in a dose-dependent manner. Additionally, silencing lncRNA-MALAT1 inhibited the expressions of osteogenesis-related marker genes and abolished the effect of SalB on osteogenesis. Also, we found that lncRNA-MALAT1 sponged miR-155-5p, and miR-155-5p directly targeted HIF-1α. Using the osteoporotic fracture healing model, our result demonstrated that local administration of SalB could promote both bone and type H vessel formation in the calluses. The mechanical test further showed that SalB could improve the mechanical properties of fractured femurs.

Conclusion

Taken together, our study reported that SalB could promote osteogenesis and type H vessel formation to accelerate osteoporotic fracture healing through the lncRNA- MALAT1/miR-155-5p/HIF-1α axis.

© 2025 Bentham Science Publishers
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2026-02-05

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References

  1. TongX. GuP. XuS. LinX. Long non-coding RNA-DANCR in human circulating monocytes: A potential biomarker associated with postmenopausal osteoporosis.Biosci. Biotechnol. Biochem.201579573273710.1080/09168451.2014.99861725660720
     [Google Scholar]
  2. ChoyM.H.V. WongR.M.Y. ChowS.K.H. LiM.C. ChimY.N. LiT.K. HoW.T. ChengJ.C.Y. CheungW.H. How much do we know about the role of osteocytes in different phases of fracture healing? A systematic review.J. Orthop. Translat.20202111112110.1016/j.jot.2019.07.00532309136
     [Google Scholar]
  3. MarmorM. AltV. LattaL. LaneJ. RebolledoB. EgolK.A. MiclauT. Osteoporotic fracture care.J. Orthop. Trauma201529Suppl. 12S53S5610.1097/BOT.000000000000046926584268
     [Google Scholar]
  4. DuplombL. DagouassatM. JourdonP. HeymannD. Concise review: Embryonic stem cells: A new tool to study osteoblast and osteoclast differentiation.Stem Cells200725354455210.1634/stemcells.2006‑039517095705
     [Google Scholar]
  5. PittengerM.F. MackayA.M. BeckS.C. JaiswalR.K. DouglasR. MoscaJ.D. MoormanM.A. SimonettiD.W. CraigS. MarshakD.R. Multilineage potential of adult human mesenchymal stem cells.Science1999284541114314710.1126/science.284.5411.14310102814
     [Google Scholar]
  6. BarkholtL. FloryE. JekerleV. Lucas-SamuelS. AhnertP. BissetL. BüscherD. FibbeW. FoussatA. KwaM. LantzO. MačiulaitisR. PalomäkiT. SchneiderC.K. SensebéL. TachdjianG. TarteK. ToscaL. SalmikangasP. Risk of tumorigenicity in mesenchymal stromal cell–based therapies—Bridging scientific observations and regulatory viewpoints.Cytotherapy201315775375910.1016/j.jcyt.2013.03.00523602595
     [Google Scholar]
  7. LiY. LiJ. ChenL. XuL. The roles of long non-coding RNA in osteoporosis.Curr. Stem Cell Res. Ther.202015763964510.2174/1574888X1566620050123573532357819
     [Google Scholar]
  8. KoppF. MendellJ.T. Functional classification and experimental dissection of long noncoding RNAs.Cell2018172339340710.1016/j.cell.2018.01.01129373828
     [Google Scholar]
  9. ZhuL. XuP.C. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression.Biochem. Biophys. Res. Commun.2013432461261710.1016/j.bbrc.2013.02.03623438432
     [Google Scholar]
  10. DouC. CaoZ. YangB. DingN. HouT. LuoF. KangF. LiJ. YangX. JiangH. XiangJ. QuanH. XuJ. DongS. Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis.Sci. Rep.2016612149910.1038/srep2149926856880
     [Google Scholar]
  11. WangY. LuoT.B. LiuL. CuiZ.Q. LncRNA LINC00311 promotes the proliferation and differentiation of osteoclasts in osteoporotic rats through the notch signaling pathway by targeting DLL3.Cell. Physiol. Biochem.20184762291230610.1159/00049153929975944
     [Google Scholar]
  12. CesanaM. CacchiarelliD. LegniniI. SantiniT. SthandierO. ChinappiM. TramontanoA. BozzoniI. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA.Cell2011147235836910.1016/j.cell.2011.09.02822000014
     [Google Scholar]
  13. LiuM.L. ZhangQ. YuanX. JinL. WangL.L. FangT.T. WangW.B. Long noncoding RNA RP4 functions as a competing endogenous RNA through miR-7-5p sponge activity in colorectal cancer.World J. Gastroenterol.20182491004101210.3748/wjg.v24.i9.100429531464
     [Google Scholar]
  14. ZhaoC.C. JiaoY. ZhangY.Y. NingJ. ZhangY.R. XuJ. WeiW. Kang-ShengG. Lnc SMAD5-AS1 as ceRNA inhibit proliferation of diffuse large B cell lymphoma via Wnt/β- catenin pathway by sponging miR-135b-5p to elevate expression of APC.Cell Death Dis.201910425210.1038/s41419‑019‑1479‑330874550
     [Google Scholar]
  15. GutschnerT. HämmerleM. DiederichsS. MALAT1 - a paradigm for long noncoding RNA function in cancer.J. Mol. Med. (Berl.)201391779180110.1007/s00109‑013‑1028‑y23529762
     [Google Scholar]
  16. LiZ.X. ZhuQ.N. ZhangH.B. HuY. WangG. ZhuY.S. MALAT1: A potential biomarker in cancer.Cancer Manag. Res.2018106757676810.2147/CMAR.S16940630584369
     [Google Scholar]
  17. HeH. ShiM. ZengX. YangJ. LiY. WuL. LiL. RETRACTED: Cardioprotective effect of salvianolic acid B on large myocardial infarction mediated by reversing upregulation of leptin, endothelin pathways, and abnormal expression of SERCA2a, phospholamban in rats.J. Ethnopharmacol.20081181354510.1016/j.jep.2008.03.00618439775
     [Google Scholar]
  18. JoeY. ZhengM. KimH.J. KimS. UddinM.J. ParkC. RyuD.G. KangS.S. RyooS. RyterS.W. ChangK.C. ChungH.T. Salvianolic acid B exerts vasoprotective effects through the modulation of heme oxygenase-1 and arginase activities.J. Pharmacol. Exp. Ther.2012341385085810.1124/jpet.111.19073622442118
     [Google Scholar]
  19. WangZ. LuoP. DaiS. LiuZ. ZhengX. ChenT. Salvianolic acid B induces apoptosis in human glioma U87 cells through p38-mediated ROS generation.Cell. Mol. Neurobiol.201333792192810.1007/s10571‑013‑9958‑z23842993
     [Google Scholar]
  20. KimD.H. ParkS.J. KimJ.M. JeonS.J. KimD.H. ChoY.W. SonK.H. LeeH.J. MoonJ.H. CheongJ.H. KoK.H. RyuJ.H. Cognitive dysfunctions induced by a cholinergic blockade and Aβ25–35 peptide are attenuated by salvianolic acid B.Neuropharmacology20116181432144010.1016/j.neuropharm.2011.08.03821903108
     [Google Scholar]
  21. WangR. YuX.Y. GuoZ.Y. WangY.J. WuY. YuanY.F. Inhibitory effects of salvianolic acid B on CCl4-induced hepatic fibrosis through regulating NF-κB/IκBα signaling.J. Ethnopharmacol.2012144359259810.1016/j.jep.2012.09.04823041223
     [Google Scholar]
  22. LeeY.W. KimD.H. JeonS.J. ParkS.J. KimJ.M. JungJ.M. LeeH.E. BaeS.G. OhH.K. Ho SonK.H. RyuJ.H. Neuroprotective effects of salvianolic acid B on an Aβ25–35 peptide-induced mouse model of Alzheimer’s disease.Eur. J. Pharmacol.20137041-3707710.1016/j.ejphar.2013.02.01523461850
     [Google Scholar]
  23. XuD. XuL. ZhouC. LeeW.Y.W. WuT. CuiL. LiG. Salvianolic acid B promotes osteogenesis of human mesenchymal stem cells through activating ERK signaling pathway.Int. J. Biochem. Cell Biol.2014511910.1016/j.biocel.2014.03.00524657587
     [Google Scholar]
  24. WangP. WangM. ZhuoT. LiY. LinW. DingL. ZhangM. ZhouC. ZhangJ. LiG. WangH. XuL. Hydroxysafflor yellow A promotes osteogenesis and bone development via epigenetically regulating β-catenin and prevents ovariectomy-induced bone loss.Int. J. Biochem. Cell Biol.202113710603310.1016/j.biocel.2021.10603334216755
     [Google Scholar]
  25. DingL. GuS. ZhouB. WangM. ZhangY. WuS. ZouH. ZhaoG. GaoZ. XuL. Ginsenoside compound K enhances fracture healing via promoting osteogenesis and angiogenesis.Front. Pharmacol.20221385539310.3389/fphar.2022.85539335462912
     [Google Scholar]
  26. LiuC. RenS. ZhaoS. WangY. LncRNA MALAT1/MiR-145 Adjusts IL-1β-induced chondrocytes viability and cartilage matrix degradation by regulating ADAMTS5 in human osteoarthritis.Yonsei Med. J.201960111081109210.3349/ymj.2019.60.11.108131637891
     [Google Scholar]
  27. YangT. LiH. ChenT. RenH. ShiP. ChenM. LncRNA MALAT1 depressed chemo-sensitivity of NSCLC cells through directly functioning on miR-197-3p/p120 catenin axis.Mol. Cells201942327028330841025
     [Google Scholar]
  28. FangB. LiY. ChenC. WeiQ. ZhengJ. LiuY. HeW. LinD. LiG. HouY. XuL. Huo Xue Tong Luo capsule ameliorates osteonecrosis of femoral head through inhibiting lncRNA-Miat.J. Ethnopharmacol.201923811186210.1016/j.jep.2019.11186230970282
     [Google Scholar]
  29. ZhengJ.Q. HuangY.N. LiY. LaiJ.Q. ChenC. lncRNA-TINCR functions as a competitive endogenous RNA to regulate the migration of mesenchymal stem cells by sponging miR-761.Biomed Res Int202020209578730
     [Google Scholar]
  30. WangM. GaoZ. ZhangY. ZhaoQ. TanX. WuS. DingL. LiuY. QinS. GuJ. XuL. Syringic acid promotes cartilage extracellular matrix generation and attenuates osteoarthritic cartilage degradation by activating TGF-β/Smad and inhibiting NF-κB signaling pathway.Phytother. Res.20243821000101210.1002/ptr.808938126609
     [Google Scholar]
  31. SunY. XuL. HuangS. HouY. LiuY. ChanK.M. PanX.H. LiG. mir-21 overexpressing mesenchymal stem cells accelerate fracture healing in a rat closed femur fracture model.BioMed Res. Int.201520151910.1155/2015/41232725879024
     [Google Scholar]
  32. XuL. HuangS. HouY. LiuY. NiM. MengF. WangK. RuiY. JiangX. LiG. Sox11-modified mesenchymal stem cells (MSCs) accelerate bone fracture healing: Sox11 regulates differentiation and migration of MSCs.FASEB J.20152941143115210.1096/fj.14‑25416925466891
     [Google Scholar]
  33. HouY. LinW. LiY. SunY. LiuY. ChenC. JiangX. LiG. XuL. De-osteogenic-differentiated mesenchymal stem cells accelerate fracture healing by mir-92b.J. Orthop. Translat.202127253210.1016/j.jot.2020.10.00933344169
     [Google Scholar]
  34. TengF. XuZ. ChenJ. ZhengG. ZhengG. LvH. WangY. WangL. ChengX. DUSP1 induces apatinib resistance by activating the MAPK pathway in gastric cancer.Oncol. Rep.20184031203122210.3892/or.2018.652029956792
     [Google Scholar]
  35. ZhouX. ZhangW. JinM. ChenJ. XuW. KongX. lncRNA MIAT functions as a competing endogenous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathy.Cell Death Dis.201787e292910.1038/cddis.2017.32128703801
     [Google Scholar]
  36. ZhaoL. ZhangH. SunQ. ZhaoA. WangC. LiuJ. WangB. Combination of baicalin and gardenoside mitigates brain damage by lowering AQP-4 expression levels in rat model of cerebral ischemia/reperfusion.Future Integr. Med.202300000000010.14218/FIM.2022.00036
     [Google Scholar]
  37. ZhangB. ArunG. MaoY.S. LazarZ. HungG. BhattacharjeeG. XiaoX. BoothC.J. WuJ. ZhangC. SpectorD.L. The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult.Cell Rep.20122111112310.1016/j.celrep.2012.06.00322840402
     [Google Scholar]
  38. WiluszJ.E. FreierS.M. SpectorD.L. 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA.Cell2008135591993210.1016/j.cell.2008.10.01219041754
     [Google Scholar]
  39. HutchinsonJ.N. EnsmingerA.W. ClemsonC.M. LynchC.R. LawrenceJ.B. ChessA. A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains.BMC Genomics2007813910.1186/1471‑2164‑8‑3917270048
     [Google Scholar]
  40. ZuoY. LiY. ZhouZ. MaM. FuK. Long non-coding RNA MALAT1 promotes proliferation and invasion via targeting miR-129-5p in triple-negative breast cancer.Biomed. Pharmacother.20179592292810.1016/j.biopha.2017.09.00528915533
     [Google Scholar]
  41. KimJ. PiaoH.L. KimB.J. YaoF. HanZ. WangY. XiaoZ. SiverlyA.N. LawhonS.E. TonB.N. LeeH. ZhouZ. GanB. NakagawaS. EllisM.J. LiangH. HungM.C. YouM.J. SunY. MaL. Long noncoding RNA MALAT1 suppresses breast cancer metastasis.Nat. Genet.201850121705171510.1038/s41588‑018‑0252‑330349115
     [Google Scholar]
  42. YangX. YangJ. LeiP. WenT. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis.Aging201911208777879110.18632/aging.10226431659145
     [Google Scholar]
  43. ChenL. FengP. ZhuX. HeS. DuanJ. ZhouD. Long non-coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells.J. Cell. Mol. Med.201620112102211010.1111/jcmm.1290427374227
     [Google Scholar]
  44. LaiL. WangG. XuL. FuY. CEBPB promotes gastrointestinal motility dysfunction after severe acute pancreatitis via the MALAT1/CIRBP/ERK axis.Mol. Immunol.20231561910.1016/j.molimm.2023.02.00136842228
     [Google Scholar]
  45. HuangJ. LiuL. FengM. anS. ZhouM. LiZ. QiJ. ShenH. Effect of CoCl2 on fracture repair in a rat model of bone fracture.Mol. Med. Rep.20151245951595610.3892/mmr.2015.412226239779
     [Google Scholar]
  46. QiaoJ. HuangJ. ZhouM. CaoG. ShenH. Inhibition of HIF-1α restrains fracture healing via regulation of autophagy in a rat model.Exp. Ther. Med.20191731884189030783464
     [Google Scholar]
  47. KomatsuD.E. HadjiargyrouM. Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair.Bone200434468068810.1016/j.bone.2003.12.02415050899
     [Google Scholar]
  48. LiW. WangK. LiuZ. DingW. HIF-1α change in serum and callus during fracture healing in ovariectomized mice.Int. J. Clin. Exp. Pathol.20158111712625755698
     [Google Scholar]
  49. KellyB.D. HackettS.F. HirotaK. OshimaY. CaiZ. Berg-DixonS. RowanA. YanZ. CampochiaroP.A. SemenzaG.L. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1.Circ. Res.200393111074108110.1161/01.RES.0000102937.50486.1B14576200
     [Google Scholar]
  50. KusumbeA.P. RamasamyS.K. AdamsR.H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone.Nature2014507749232332810.1038/nature1314524646994
     [Google Scholar]
  51. RamasamyS.K. KusumbeA.P. WangL. AdamsR.H. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone.Nature2014507749237638010.1038/nature1314624647000
     [Google Scholar]
  52. DingW. XuC. ZhangY. ChenH. Advances in the understanding of the role of type-H vessels in the pathogenesis of osteoporosis.Arch. Osteoporos.2020151510.1007/s11657‑019‑0677‑z31897773
     [Google Scholar]
  53. WangL. ZhouF. ZhangP. WangH. QuZ. JiaP. YaoZ. ShenG. LiG. ZhaoG. LiJ. MaoY. XieZ. XuW. XuY. XuY. Human type H vessels are a sensitive biomarker of bone mass.Cell Death Dis.201785e276010.1038/cddis.2017.3628471445
     [Google Scholar]
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Salvianolic Acid B Accelerates Osteoporotic Fracture Healing via LncRNA-MALAT1/miR-155-5p/HIF1A Axis
Curr Stem Cell Res Ther 20, 759 (2025); https://doi.org/10.2174/011574888X304709240628092958
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  • Article Type:     Research Article
Keyword(s): Salvianolic acid B (SalB); HIF-1α, fracture, mesenchymal stem cells; lncRNA-MALAT1; osteoporotic fracture

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