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image of Bone Marrow Mesenchymal Stem Cell Senescence in the Development of Osteoporosis: Mechanisms, Interventions, and Future Directions

Abstract

Osteoporosis, a significant age-related disease, is marked by diminished bone density and an elevated risk of fractures, representing a considerable global health challenge. Bone marrow mesenchymal ste

m cells (BMSCs) are essential in maintaining bone integrity through their differentiation into osteoblasts, which are crucial for bone formation. Nevertheless, the aging of BMSCs diminishes their regenerative abilities and intensifies inflammation, thereby playing a critical role in osteoporosis pathogenesis. This review explores the intricate mechanisms of BMSC senescence and its influence on osteoporosis, detailing cellular and molecular markers, such as oxidative stress, the senescence-associated secretory phenotype (SASP), and pivotal signaling pathways, including P53, PI3K/mTOR, and autophagy. We assess current interventions aimed at reducing BMSC senescence, with an emphasis on pharmacological methods like melatonin and antioxidants, alongside non-pharmacological strategies, such as exercise and dietary supplementation with omega-3 fatty acids. Furthermore, the challenges and limitations of translating these strategies into clinical applications are addressed, highlighting the necessity for personalized medicine to accommodate treatment outcome variability. Future research directions should focus on emerging therapeutic targets and novel interventions, such as gene editing technologies and advanced tissue engineering techniques. By integrating these strategies, this review endeavors to enhance the understanding and treatment of osteoporosis, emphasizing the critical need to target BMSC senescence to develop effective therapies.

This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-03-27
2025-11-04
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References

  1. Snyder S. Postmenopausal osteoporosis. N. Engl. J. Med. 2024 390 7 673 676 10.1056/NEJMc2314624 38354156
    [Google Scholar]
  2. Thuilier E. Carey J. Dempsey M. Dingliana J. Whelan B. Brennan A. Virtual rehabilitation for patients with osteoporosis or other musculoskeletal disorders: A systematic review. Virtual Real. (Walth. Cross) 2024 28 2 93 10.1007/s10055‑024‑00980‑7 38595908
    [Google Scholar]
  3. Zhao Y. He J. Qiu T. Zhang H. Liao L. Su X. Epigenetic therapy targeting bone marrow mesenchymal stem cells for age-related bone diseases. Stem Cell Res. Ther. 2022 13 1 201 10.1186/s13287‑022‑02852‑w 35578312
    [Google Scholar]
  4. Jin J. Huang R. Chang Y. Yi X. Roles and mechanisms of optineurin in bone metabolism. Biomed. Pharmacother. 2024 172 116258 10.1016/j.biopha.2024.116258 38350370
    [Google Scholar]
  5. Ning K. Liu S. Yang B. Wang R. Man G. Wang D. Xu H. Update on the effects of energy metabolism in bone marrow mesenchymal stem cells differentiation. Mol. Metab. 2022 58 101450 10.1016/j.molmet.2022.101450 35121170
    [Google Scholar]
  6. Mirshahi P. Rafii A. Vincent L. Berthaut A. Varin R. Kalantar G. Marzac C. Calandini O.A. Marie J-P. Soria C. Soria J. Mirshahi M. Vasculogenic mimicry of acute leukemic bone marrow stromal cells. Leukemia 2009 23 6 1039 1048 10.1038/leu.2009.10 19340002
    [Google Scholar]
  7. Heo C.H. Bak S.Y. Kim Y. Ok M.R. Kim S.Y. Development of an integrin αv-based universal marker, capable of both prediction and direction of stem cell fate. Acta Biomater. 2023 166 291 300 10.1016/j.actbio.2023.04.044 37137404
    [Google Scholar]
  8. Lin H. Sohn J. Shen H. Langhans M.T. Tuan R.S. Bone marrow mesenchymal stem cells: Aging and tissue engineering applications to enhance bone healing. Biomaterials 2019 203 96 110 10.1016/j.biomaterials.2018.06.026 29980291
    [Google Scholar]
  9. Wu J. Hu M. Jiang H. Ma J. Xie C. Zhang Z. Zhou X. Zhao J. Tao Z. Meng Y. Cai Z. Song T. Zhang C. Gao R. Cai C. Song H. Gao Y. Lin T. Wang C. Zhou X. Endothelial cell‐derived lactate triggers bone mesenchymal stem cell histone lactylation to attenuate osteoporosis. Adv. Sci. (Weinh.) 2023 10 31 2301300 10.1002/advs.202301300 37752768
    [Google Scholar]
  10. Huang M. Xu S. Liu L. Zhang M. Guo J. Yuan Y. Xu J. Chen X. Zou J. m6A methylation regulates osteoblastic differentiation and bone remodeling. Front. Cell Dev. Biol. 2021 9 783322 10.3389/fcell.2021.783322 34993198
    [Google Scholar]
  11. Wang J. Zhu Q. Cao D. Peng Q. Zhang X. Li C. Zhang C. Zhou B.O. Yue R. Bone marrow-derived IGF-1 orchestrates maintenance and regeneration of the adult skeleton. Proc. Natl. Acad. Sci. USA 2023 120 1 e2203779120 10.1073/pnas.2203779120 36577075
    [Google Scholar]
  12. Wang Z.X. Luo Z.W. Li F.X.Z. Cao J. Rao S.S. Liu Y.W. Wang Y.Y. Zhu G.Q. Gong J.S. Zou J.T. Wang Q. Tan Y.J. Zhang Y. Hu Y. Li Y.Y. Yin H. Wang X.K. He Z.H. Ren L. Liu Z.Z. Hu X.K. Yuan L.Q. Xu R. Chen C.Y. Xie H. Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox. Nat. Commun. 2022 13 1 1453 10.1038/s41467‑022‑29191‑x 35304471
    [Google Scholar]
  13. Hsu Y.C. Wu Y.T. Yu T.H. Wei Y.H. Mitochondria in mesenchymal stem cell biology and cell therapy: From cellular differentiation to mitochondrial transfer. Semin. Cell Dev. Biol. 2016 52 119 131 10.1016/j.semcdb.2016.02.011 26868759
    [Google Scholar]
  14. Liu C. Xiong Q. Li Q. Lin W. Jiang S. Zhang D. Wang Y. Duan X. Gong P. Kang N. CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling. Nat. Commun. 2022 13 1 1989 10.1038/s41467‑022‑29633‑6 35418650
    [Google Scholar]
  15. Guo Y. Jia X. Cui Y. Song Y. Wang S. Geng Y. Li R. Gao W. Fu D. Sirt3-mediated mitophagy regulates AGEs-induced BMSCs senescence and senile osteoporosis. Redox Biol. 2021 41 101915 10.1016/j.redox.2021.101915 33662874
    [Google Scholar]
  16. Liu F. Yuan L. Li L. Yang J. Liu J. Chen Y. Zhang J. Lu Y. Yuan Y. Cheng J. S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis. Pharmacol. Res. 2023 192 106788 10.1016/j.phrs.2023.106788 37146925
    [Google Scholar]
  17. Huo S. Tang X. Chen W. Gan D. Guo H. Yao Q. Liao R. Huang T. Wu J. Yang J. Xiao G. Han X. Epigenetic regulations of cellular senescence in osteoporosis. Ageing Res. Rev. 2024 99 102235 10.1016/j.arr.2024.102235 38367814
    [Google Scholar]
  18. Saeed H. Iqtedar M. Bone marrow stromal cell (BMSC) and skeletal aging: Role of telomerase enzyme. Pak. J. Pharm. Sci. 2014 27 2 321 333 [published Online First: 2014/03/01]. 24577922
    [Google Scholar]
  19. Abdul-Aziz A. Devine R.D. Lyberger J.M. Chang H. Kovacs A. Lerma J.R. Rogers A.M. Byrd J.C. Hertlein E. Behbehani G.K. Mass cytometry as a tool for investigating senescence in multiple model systems. Cells 2023 12 16 2045 10.3390/cells12162045 37626855
    [Google Scholar]
  20. Wang X. Liu C. Xu F. Cui L. Tan S. Chen R. Yang L. Huang J. Effects of neuritin on the migration, senescence and proliferation of human bone marrow mesenchymal stem cells. Cell. Mol. Biol. Lett. 2015 20 3 466 474 10.1515/cmble‑2015‑0026 26208391
    [Google Scholar]
  21. Suo J. Zou S. Wang J. Han Y. Zhang L. Lv C. Jiang B. Ren Q. Chen L. Yang L. Ji P. Zheng X. Hu P. Zou W. The RNA-binding protein Musashi2 governs osteoblast-adipocyte lineage commitment by suppressing PPARγ signaling. Bone Res. 2022 10 1 31 10.1038/s41413‑022‑00202‑3 35301280
    [Google Scholar]
  22. Yang N. Sun H. Xue Y. Zhang W. Wang H. Tao H. Liang X. Li M. Xu Y. Chen L. Zhang L. Huang L. Geng D. Inhibition of MAGL activates the Keap1/Nrf2 pathway to attenuate glucocorticoid‐induced osteonecrosis of the femoral head. Clin. Transl. Med. 2021 11 6 e447 10.1002/ctm2.447 34185425
    [Google Scholar]
  23. Ma J. Shen M. Yue D. Wang W. Gao F. Wang B. Extracellular vesicles from BMSCs prevent glucocorticoid-induced bmecs injury by regulating autophagy via the PI3K/Akt/mTOR pathway. Cells 2022 11 13 2104 10.3390/cells11132104 35805188
    [Google Scholar]
  24. Lin M. Liu X. Zheng H. Huang X. Wu Y. Huang A. Zhu H. Hu Y. Mai W. Huang Y. IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway. Stem Cell Res. Ther. 2020 11 1 22 10.1186/s13287‑019‑1544‑y 31918758
    [Google Scholar]
  25. Hu M. Xing L. Zhang L. Liu F. Wang S. Xie Y. Wang J. Jiang H. Guo J. Li X. Wang J. Sui L. Li C. Liu D. Liu Z. NAP1L2 drives mesenchymal stem cell senescence and suppresses osteogenic differentiation. Aging Cell 2022 21 2 e13551 10.1111/acel.13551 35032339
    [Google Scholar]
  26. Fulzele S. Mendhe B. Khayrullin A. Johnson M. Kaiser H. Liu Y. Isales C.M. Hamrick M.W. Muscle-derived miR-34a increases with age in circulating extracellular vesicles and induces senescence of bone marrow stem cells. Aging (Albany NY) 2019 11 6 1791 1803 10.18632/aging.101874 30910993
    [Google Scholar]
  27. Xie Y. Han N. Li F. Wang L. Liu G. Hu M. Wang S. Wei X. Guo J. Jiang H. Wang J. Li X. Wang Y. Wang J. Bian X. Zhu Z. Zhang H. Liu C. Liu X. Liu Z. Melatonin enhances osteoblastogenesis of senescent bone marrow stromal cells through NSD2‐mediated chromatin remodelling. Clin. Transl. Med. 2022 12 2 e746 10.1002/ctm2.746 35220680
    [Google Scholar]
  28. Liu F. Yuan Y. Bai L. Yuan L. Li L. Liu J. Chen Y. Lu Y. Cheng J. Zhang J. LRRc17 controls BMSC senescence via mitophagy and inhibits the therapeutic effect of BMSCs on ovariectomy-induced bone loss. Redox Biol. 2021 43 101963 10.1016/j.redox.2021.101963 33865167
    [Google Scholar]
  29. Xiao Y. Cai G.P. Feng X. Li Y.J. Guo W.H. Guo Q. Huang Y. Su T. Li C.J. Luo X.H. Zheng Y.J. Yang M. Splicing factor YBX1 regulates bone marrow stromal cell fate during aging. EMBO J. 2023 42 9 e111762 10.15252/embj.2022111762 36943004
    [Google Scholar]
  30. Li X. Wang X. Zhang C. Wang J. Wang S. Hu L. Dysfunction of metabolic activity of bone marrow mesenchymal stem cells in aged mice. Cell Prolif. 2022 55 3 e13191 10.1111/cpr.13191 35088483
    [Google Scholar]
  31. Chang T.C. Hsu M.F. Wu K.K. High glucose induces bone marrow-derived mesenchymal stem cell senescence by upregulating autophagy. PLoS One 2015 10 5 e0126537 10.1371/journal.pone.0126537 25961745
    [Google Scholar]
  32. Mei Q. Li K. Tang T. Cai S. Liu Y. Wang X. Jia Y. Zhang L. Li H. Song H. Zhai J. Xiang W. miR‐203‐3p promotes senescence of mouse bone marrow mesenchymal stem cells via downregulation of Pbk. Aging Cell 2024 23 11 e14293 10.1111/acel.14293 39123275
    [Google Scholar]
  33. Liang F. Luo Y. Guo Z. Qian Q. Meng X.B. Mo Z.H. MicroRNA‐139‐5p mediates BMSCsimpairment in diabetes by targeting HOXA9/c‐Fos. FASEB J. 2023 37 1 e22697 10.1096/fj.202201059R 36527387
    [Google Scholar]
  34. Long H. Sun B. Cheng L. Zhao S. Zhu Y. Zhao R. Zhu J. miR-139-5p represses BMSC osteogenesis via targeting Wnt/β-catenin signaling pathway. DNA Cell Biol. 2017 36 8 715 724 10.1089/dna.2017.3657 28622009
    [Google Scholar]
  35. Wang D. Cai G. Wang H. He J. TRAF3, a target of MicroRNA-363-3p, suppresses senescence and regulates the balance between osteoblastic and adipocytic differentiation of rat bone marrow-derived mesenchymal stem cells. Stem Cells Dev. 2020 29 11 737 745 10.1089/scd.2019.0276 32111144
    [Google Scholar]
  36. Xiao F. Peng J. Li Y. Zhou X. Ma D. Dai L. Yuan J. Chen X. Wang C. Small noncoding RNAome changes during human bone marrow mesenchymal stem cells senescence in vitro. Front. Endocrinol. (Lausanne) 2022 13 808223 10.3389/fendo.2022.808223 35634512
    [Google Scholar]
  37. Huang Y. Wang S. Hu D. Zhang L. Shi S. ALKBH5 regulates etoposide-induced cellular senescence and osteogenic differentiation in osteoporosis through mediating the m6A modification of VDAC3. Sci. Rep. 2024 14 1 23461 10.1038/s41598‑024‑75033‑9 39379688
    [Google Scholar]
  38. Wu W. Fu J. Gu Y. Wei Y. Ma P. Wu J. JAK2/STAT3 regulates estrogen-related senescence of bone marrow stem cells. J. Endocrinol. 2020 245 1 141 153 10.1530/JOE‑19‑0518 32045363
    [Google Scholar]
  39. Zheng Y. Lei Y. Hu C. Hu C. p53 regulates autophagic activity in senescent rat mesenchymal stromal cells. Exp. Gerontol. 2016 75 64 71 10.1016/j.exger.2016.01.004 26792455
    [Google Scholar]
  40. Zheng Y. Wu S. Ke H. Peng S. Hu C. Secretion of IL-6 and IL-8 in the senescence of bone marrow mesenchymal stem cells is regulated by autophagy via FoxO3a. Exp. Gerontol. 2023 172 112062 10.1016/j.exger.2022.112062 36526098
    [Google Scholar]
  41. Chen K. Tao H. Xiao H. Chu M. Zhu P. Lv S. Huang L. Geng D. Identification of ferroptosis/autophagy-related genes and potential underlying mechanisms involved in the effect of BMSC senescence on the osteogenic differentiation of aging BMSCs. Genes Dis. 2025 12 1 101259 10.1016/j.gendis.2024.101259 39493784
    [Google Scholar]
  42. Al-Azab M. Wang B. Elkhider A. Walana W. Li W. Yuan B. Ye Y. Tang Y. Almoiliqy M. Adlat S. Wei J. Zhang Y. Li X. Indian Hedgehog regulates senescence in bone marrow-derived mesenchymal stem cell through modulation of ROS/mTOR/4EBP1, p70S6K1/2 pathway. Aging (Albany NY) 2020 12 7 5693 5715 10.18632/aging.102958 32235006
    [Google Scholar]
  43. Xu Y. Chang L. Chen Y. Dan Z. Zhou L. Tang J. Deng L. Tang G. Li C. USP26 combats age‐related declines in self‐renewal and multipotent differentiation of BMSC by maintaining mitochondrial homeostasis. Adv. Sci. (Weinh.) 2024 11 44 2406428 10.1002/advs.202406428 39377219
    [Google Scholar]
  44. Farr J.N. Xu M. Weivoda M.M. Monroe D.G. Fraser D.G. Onken J.L. Negley B.A. Sfeir J.G. Ogrodnik M.B. Hachfeld C.M. LeBrasseur N.K. Drake M.T. Pignolo R.J. Pirtskhalava T. Tchkonia T. Oursler M.J. Kirkland J.L. Khosla S. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 2017 23 9 1072 1079 10.1038/nm.4385 28825716
    [Google Scholar]
  45. Wang Y. Che L. Chen X. He Z. Song D. Yuan Y. Liu C. Repurpose dasatinib and quercetin: Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration. Bioact. Mater. 2023 25 13 28 10.1016/j.bioactmat.2023.01.009 37056256
    [Google Scholar]
  46. Chen J. Kuang S. Cen J. Zhang Y. Shen Z. Qin W. Huang Q. Wang Z. Gao X. Huang F. Lin Z. Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure. Int. J. Oral Sci. 2024 16 1 41 10.1038/s41368‑024‑00309‑9 38777841
    [Google Scholar]
  47. Patel D. Potter M. Anaya J.M. McGee-Lawrence M.E. Hamrick M.W. Hill W.D. Isales C.M. Fulzele S. Kynurenine induces an age-related phenotype in bone marrow stromal cells. Mech. Ageing Dev. 2021 195 111464 10.1016/j.mad.2021.111464 33631183
    [Google Scholar]
  48. Huang H. Qian Y. Feng Y. Wang Y. Qian P. Xu F. Wang Q. Erxian Decoction‐induced serum exosomes slowed bone marrow mesenchymal stem cell senescence through mitophagy. J. Gene Med. 2024 26 1 e3617 10.1002/jgm.3617 37935422
    [Google Scholar]
  49. Yi L. Ju Y. He Y. Yin X. Xu Y. Weng T. Intraperitoneal injection of Desferal® alleviated the age-related bone loss and senescence of bone marrow stromal cells in rats. Stem Cell Res. Ther. 2021 12 1 45 10.1186/s13287‑020‑02112‑9 33413663
    [Google Scholar]
  50. Wang J. Liu L. Ding Z. Luo Q. Ju Y. Song G. Exogenous NAD+ postpones the D-gal-induced senescence of bone marrow-derived mesenchymal stem cells via Sirt1 signaling. Antioxidants 2021 10 2 254 10.3390/antiox10020254 33562281
    [Google Scholar]
  51. Liu D.Y. Wu J. Zhou H.Y. Lv J.X. Cai K.Z. Tang C.B. Phytic acid improves osteogenesis and inhibits the senescence of human bone marrow mesenchymal stem cells under high-glucose conditions via the ERK pathway. Chem. Biol. Interact. 2024 387 110818 10.1016/j.cbi.2023.110818 38000455
    [Google Scholar]
  52. Wang Y. Jin S. Guo Y. Zhu L. Lu Y. Li J. Heng B.C. Liu Y. Deng X. Cordycepin‐loaded dental pulp stem cell‐derived exosomes promote aged bone repair by rejuvenating senescent mesenchymal stem cells and endothelial cells. Adv. Healthc. Mater. 2025 14 2 2402909 10.1002/adhm.202402909 39551987
    [Google Scholar]
  53. Zhai Y. Zhang Y. Xu K. Wang T. Zhiqun Bian Qu L. Wu F. Hu Z. Chang X. Li H. Zhang C. Li C. Shi C. Cordycepin ameliorates spaceflight-induced osteoporosis by preventing BMSCs oxidative stress and senescence via interacting with PI3K p110α and regulating PI3K/Akt/FOXO3 signalling. Free Radic. Biol. Med. 2025 228 108 125 10.1016/j.freeradbiomed.2024.12.044 39722302
    [Google Scholar]
  54. Liang B. Chen X. Li M. Zhang L. Yang X. Shi L. Gong Y. Gong Y. Xu H. Wu X. Jin Z. Wang Y. Liu L. Yi X. Xie L. Zhong H. Shen C. Wang Y. Yang L. Liuwei Dihuang pills attenuate ovariectomy-induced bone loss by alleviating bone marrow mesenchymal stem cell (BMSC) senescence via the Yes-associated protein (YAP)-autophagy axis. Pharm. Biol. 2024 62 1 42 52 10.1080/13880209.2023.2291675 38112463
    [Google Scholar]
  55. Wei F. Neal C.J. Sakthivel T.S. Fu Y. Omer M. Adhikary A. Ward S. Ta K.M. Moxon S. Molinari M. Asiatico J. Kinzel M. Yarmolenko S.N. San Cheong V. Orlovskaya N. Ghosh R. Seal S. Coathup M. A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme. Bioact. Mater. 2023 21 547 565 10.1016/j.bioactmat.2022.09.011 36185749
    [Google Scholar]
  56. Bai J. Wang Y. Wang J. Zhai J. He F. Zhu G. Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling. Am. J. Physiol. Cell Physiol. 2020 318 5 C1005 C1017 10.1152/ajpcell.00520.2019 32233952
    [Google Scholar]
  57. Sen B. Xie Z. Case N. Ma M. Rubin C. Rubin J. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable beta-catenin signal. Endocrinology 2008 149 12 6065 6075 10.1210/en.2008‑0687 18687779
    [Google Scholar]
  58. Casado-Díaz A. Ferreiro-Vera C. Priego-Capote F. Dorado G. Luque-de-Castro M.D. Quesada-Gómez J.M. Effects of arachidonic acid on the concentration of hydroxyeicosatetraenoic acids in culture media of mesenchymal stromal cells differentiating into adipocytes or osteoblasts. Genes Nutr. 2014 9 1 375 10.1007/s12263‑013‑0375‑1 24338342
    [Google Scholar]
  59. El Assaad N. Chebly A. Salame R. Achkar R. Bou Atme N. Akouch K. Rafoul P. Hanna C. Abou Zeid S. Ghosn M. Khalil C. Anti-aging based on stem cell therapy: A scoping review. World J. Exp. Med. 2024 14 3 97233 10.5493/wjem.v14.i3.97233 39312703
    [Google Scholar]
  60. Ding S. Ren T. Song S. Peng C. Liu C. Wu J. Chang X. Combined application of mesenchymal stem cells and different glucocorticoid dosing alleviates osteoporosis in SLE murine models. Immun. Inflamm. Dis. 2024 12 6 e1319 10.1002/iid3.1319 38888448
    [Google Scholar]
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  • Article Type:
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Keywords: Bone marrow mesenchymal stem cells ; cell senescence ; osteoporosis
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