Application Strategies of Bone Marrow Mesenchymal Stromal Cells in Bone-Related Diseases

Abstract

Bone-related diseases (e.g., osteoporosis, osteoarthritis and fractures) exhibit a rising global incidence, imposing significant burdens on both quality of life and healthcare systems. Conventional therapeutic approaches, including anti-resorptive drugs and surgical interventions, face limitations such as long-term medication requirements, adverse effects (e.g., bisphosphonate-related osteonecrosis of the jaw) and suboptimal efficacy. Bone marrow mesenchymal stromal cells (BMSCs) have emerged as a promising therapeutic alternative due to their accessibility, multi-lineage differentiation potential, immunomodulatory properties and homing capacity. However, challenges such as disease complexity, mechanistic heterogeneity and therapeutic inconsistency hinder their clinical translation. Recent advances in genetic engineering, preconditioning strategies, bone tissue engineering (e.g., three-dimensional [3D] scaffolding), extracellular vesicle-based therapies and epigenetic regulation (e.g., histone modification) have significantly enhanced the therapeutic effects of BMSCs. Furthermore, cutting-edge technologies like organoids and 3D bioprinting, which stem from advances in tissue engineering, offer novel avenues for clinical applications. Given these rapid developments, this review systematically summarises BMSC-based treatment strategies for bone-related diseases, discusses current challenges and outlines future directions to advance translational research.

Keywords

bone marrow mesenchymal stromal cells (BMSCs) / bone-related diseases / osteogenic differentiation / therapeutic strategies

References

[1] L. Wang, W. Yu, X. Yin, et al., “Prevalence of Osteoporosis and Fracture in China: The China Osteoporosis Prevalence Study,” JAMA Network Open 4 (2021): e2121106, https://doi.org/10.1001/jamanetworkopen.2021.21106.

[2] GBD 2019 Fracture Collaborators, “Global, Regional, and National Burden of Bone Fractures in 204 Countries and Territories, 1990-2019: A Systematic Analysis From the Global Burden of Disease Study 2019,” Lancet Healthy Longevity 2 (2021): e580–e592, https://doi.org/10.1016/s2666-7568(21)00172-0.

[3] F. Cao, Z. Xu, X. X. Li, et al., “Trends and Cross-Country Inequalities in the Global Burden of Osteoarthritis, 1990-2019: A Population-Based Study,” Ageing Research Reviews 99 (2024): 102382, https://doi.org/10.1016/j.arr.2024.102382.

[4] K. E. Ensrud and C. J. Crandall, “Osteoporosis,” Annals of Internal Medicine 167 (2017): 17–32, https://doi.org/10.7326/aitc201708010.

[5] T. A. Einhorn and L. C. Gerstenfeld, “Fracture Healing: Mechanisms and Interventions,” Nature Reviews Rheumatology 11 (2015): 45–54, https://doi.org/10.1038/nrrheum.2014.164.

[6] S. Glyn-Jones, A. J. R. Palmer, R. Agricola, et al., “Osteoarthritis,” Lancet 386 (2015): 376–387, https://doi.org/10.1016/s0140-6736(14)60802-3.

[7] A. J. Friedenstein, “Humoral Nature of Osteogenic Activity of Transitional Epithelium,” Nature 194 (1962): 698–699, https://doi.org/10.1038/194698a0.

[8] Y. Lu, Y. Han, L. Zhou, et al., “A Comparative Study of Mouse Bone Marrow Mesenchymal Stem Cells Isolated Using Three Easy-to-Perform Approaches,” FEBS Open Bio 12 (2022): 2154–2165, https://doi.org/10.1002/2211-5463.13493.

[9] M. F. Pittenger, A. M. Mackay, S. C. Beck, et al., “Multilineage Potential of Adult Human Mesenchymal Stem Cells,” Science 284 (1999): 143–147, https://doi.org/10.1126/science.284.5411.143.

[10] Y. You, J. Liu, L. Zhang, et al., “WTAP-Mediated m(6)A Modification Modulates Bone Marrow Mesenchymal Stem Cells Differentiation Potential and Osteoporosis,” Cell Death & Disease 14 (2023): 33, https://doi.org/10.1038/s41419-023-05565-x.

[11] J. Liu, X. Bao, J. Huang, et al., “TMEM135 Maintains the Equilibrium of Osteogenesis and Adipogenesis by Regulating Mitochondrial Dynamics,” Metabolism 152 (2024): 155767, https://doi.org/10.1016/j.metabol.2023.155767.

[12] S. J. Zhao, F. Q. Kong, J. Jie, et al., “Macrophage MSR1 Promotes BMSC Osteogenic Differentiation and M2-Like Polarization by Activating PI3K/AKT/GSK3β/β-Catenin Pathway,” Theranostics 10 (2020): 17–35, https://doi.org/10.7150/thno.36930.

[13] Y. Guo, X. Chi, Y. Wang, et al., “Mitochondria Transfer Enhances Proliferation, Migration, and Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cell and Promotes Bone Defect Healing,” Stem Cell Research & Therapy 11 (2020): 245, https://doi.org/10.1186/s13287-020-01704-9.

[14] B. Cai, D. Lin, Y. Li, et al., “N2-Polarized Neutrophils Guide Bone Mesenchymal Stem Cell Recruitment and Initiate Bone Regeneration: A Missing Piece of the Bone Regeneration Puzzle,” Advanced Science 8 (2021): e2100584, https://doi.org/10.1002/advs.202100584.

[15] M. François, R. Romieu-Mourez, M. Li, and J. Galipeau, “Human MSC Suppression Correlates With Cytokine Induction of Indoleamine 2,3-Dioxygenase and Bystander M2 Macrophage Differentiation,” Molecular Therapy 20 (2012): 187–195, https://doi.org/10.1038/mt.2011.189.

[16] C. Shen, J. Wang, G. Li, et al., “Boosting Cartilage Repair With Silk Fibroin-DNA Hydrogel-Based Cartilage Organoid Precursor,” Bioactive Materials 35 (2024): 429–444, https://doi.org/10.1016/j.bioactmat.2024.02.016.

[17] K. Zha, M. Tan, Y. Hu, et al., “Regulation of Metabolic Microenvironment With a Nanocomposite Hydrogel for Improved Bone Fracture Healing,” Bioactive Materials 37 (2024): 424–438, https://doi.org/10.1016/j.bioactmat.2024.03.025.

[18] J. Gao, H. Pei, F. Lv, et al., “JD-312—A Novel Small Molecule That Facilitates Cartilage Repair and Alleviates Osteoarthritis Progression,” Journal of Orthopaedic Translation 44 (2024): 60–71, https://doi.org/10.1016/j.jot.2023.11.007.

[19] L. Bai, G. Tao, M. Feng, et al., “Hydrogel Drug Delivery Systems for Bone Regeneration,” Pharmaceutics 15 (2023): 1334, https://doi.org/10.3390/pharmaceutics15051334.

[20] L. M. Lei, F.-X.-Z. Li, X. Lin, et al., “Cold Exposure-Induced Plasma Exosomes Impair Bone Mass by Inhibiting Autophagy,” Journal of Nanobiotechnology 22 (2024): 361, https://doi.org/10.1186/s12951-024-02640-z.

[21] Y. Zhou, P. Zhu, S. Shen, et al., “Overexpression of Fibroblast Growth Factor Receptor 2 in Bone Marrow Mesenchymal Stem Cells Enhances Osteogenesis and Promotes Critical Cranial Bone Defect Regeneration,” Frontiers in Cell and Development Biology 11 (2023): 1208239, https://doi.org/10.3389/fcell.2023.1208239.

[22] B. György, T. G. Szabó, M. Pásztói, et al., “Membrane Vesicles, Current State-of-the-Art: Emerging Role of Extracellular Vesicles,” Cellular and Molecular Life Sciences 68 (2011): 2667–2688, https://doi.org/10.1007/s00018-011-0689-3.

[23] R. Phillips, “Allogeneic iPSC-Derived Organoids Repair Articular Cartilage,” Nature Reviews Rheumatology 19 (2023): 196, https://doi.org/10.1038/s41584-023-00937-1.

[24] J. Cao, L. Jin, Z. Q. Yan, et al., “Reassessing Endothelial-to-Mesenchymal Transition in Mouse Bone Marrow: Insights From Lineage Tracing Models,” Nature Communications 14 (2023): 8461, https://doi.org/10.1038/s41467-023-44312-w.

[25] F. Liu, L. Yuan, L. Li, et al., “S-Sulfhydration of SIRT3 Combats BMSC Senescence and Ameliorates Osteoporosis via Stabilizing Heterochromatic and Mitochondrial Homeostasis,” Pharmacological Research 192 (2023): 106788, https://doi.org/10.1016/j.phrs.2023.106788.

[26] M. Soleimani and S. Nadri, “A Protocol for Isolation and Culture of Mesenchymal Stem Cells From Mouse Bone Marrow,” Nature Protocols 4 (2009): 102–106, https://doi.org/10.1038/nprot.2008.221.

[27] L. Renesme, K. D. Cobey, M. M. Lalu, et al., “Delphi-Driven Consensus Definition for Mesenchymal Stromal Cells and Clinical Reporting Guidelines for Mesenchymal Stromal Cell-Based Therapeutics,” Cytotherapy 27 (2025): 146–168, https://doi.org/10.1016/j.jcyt.2024.10.008.

[28] Z. Li, C. Zhang, L. P. Weiner, Y. Zhang, and J. F. Zhong, “Molecular Characterization of Heterogeneous Mesenchymal Stem Cells With Single-Cell Transcriptomes,” Biotechnology Advances 31 (2013): 312–317, https://doi.org/10.1016/j.biotechadv.2012.12.003.

[29] S. Liu, D. F. Stroncek, Y. Zhao, et al., “Single Cell Sequencing Reveals Gene Expression Signatures Associated With Bone Marrow Stromal Cell Subpopulations and Time in Culture,” Journal of Translational Medicine 17 (2019): 23, https://doi.org/10.1186/s12967-018-1766-2.

[30] M. Y. Hoover, T. H. Ambrosi, H. M. Steininger, et al., “Purification and Functional Characterization of Novel Human Skeletal Stem Cell Lineages,” Nature Protocols 18 (2023): 2256–2282, https://doi.org/10.1038/s41596-023-00836-5.

[31] Z. Wang, X. Li, J. Yang, et al., “Single-Cell RNA Sequencing Deconvolutes the In Vivo Heterogeneity of Human Bone Marrow-Derived Mesenchymal Stem Cells,” International Journal of Biological Sciences 17 (2021): 4192–4206, https://doi.org/10.7150/ijbs.61950.

[32] D. Zhu, J. Gao, C. Tang, Z. Xu, and T. Sun, “Single-Cell RNA Sequencing of Bone Marrow Mesenchymal Stem Cells From the Elderly People,” International Journal of Stem Cells 15 (2022): 173–182, https://doi.org/10.15283/ijsc21042.

[33] S. Wu, S. Ohba, and Y. Matsushita, “Single-Cell RNA-Sequencing Reveals the Skeletal Cellular Dynamics in Bone Repair and Osteoporosis,” International Journal of Molecular Sciences 24 (2023): 9814, https://doi.org/10.3390/ijms24129814.

[34] O. Levy, R. Kuai, E. M. J. Siren, et al., “Shattering Barriers Toward Clinically Meaningful MSC Therapies,” Science Advances 6 (2020): eaba6884, https://doi.org/10.1126/sciadv.aba6884.

[35] Y. K. Yang, C. R. Ogando, C. Wang See, T. Y. Chang, and G. A. Barabino, “Changes in Phenotype and Differentiation Potential of Human Mesenchymal Stem Cells Aging In Vitro,” Stem Cell Research & Therapy 9 (2018): 131, https://doi.org/10.1186/s13287-018-0876-3.

[36] E. Fernandez-Rebollo, J. Franzen, R. Goetzke, et al., “Senescence-Associated Metabolomic Phenotype in Primary and iPSC-Derived Mesenchymal Stromal Cells,” Stem Cell Reports 14 (2020): 201–209, https://doi.org/10.1016/j.stemcr.2019.12.012.

[37] M. Chen, H. Liang, M. Wu, et al., “Fgf9 Regulates Bone Marrow Mesenchymal Stem Cell Fate and Bone-Fat Balance in Osteoporosis by PI3K/AKT/Hippo and MEK/ERK Signaling,” International Journal of Biological Sciences 20 (2024): 3461–3479, https://doi.org/10.7150/ijbs.94863.

[38] T. Wu, H. Tang, J. Yang, et al., “METTL3-m(6) A Methylase Regulates the Osteogenic Potential of Bone Marrow Mesenchymal Stem Cells in Osteoporotic Rats via the Wnt Signalling Pathway,” Cell Proliferation 55 (2022): e13234, https://doi.org/10.1111/cpr.13234.

[39] Y. Gao, Y. Zou, D. Sokolowskei, et al., “Nr4a1 Enhances Wnt4 Transcription to Promote Mesenchymal Stem Cell Osteogenesis and Alleviates Inflammation-Inhibited Bone Regeneration,” Molecular Therapy 32 (2024): 1479–1496, https://doi.org/10.1016/j.ymthe.2024.02.034.

[40] G. Cai, Y. Lu, W. Zhong, et al., “Piezo1-Mediated M2 Macrophage Mechanotransduction Enhances Bone Formation Through Secretion and Activation of Transforming Growth Factor-β1,” Cell Proliferation 56 (2023): e13440, https://doi.org/10.1111/cpr.13440.

[41] J. Li, J. Li, Y. Wei, et al., “Ion Release Behavior of Vanadium-Doped Mesoporous Bioactive Glass Particles and the Effect of the Released Ions on Osteogenic Differentiation of BMSCs via the FAK/MAPK Signaling Pathway,” Journal of Materials Chemistry B 9 (2021): 7848–7865, https://doi.org/10.1039/d1tb01479j.

[42] K. Li, L. Liu, H. Liu, et al., “Hippo/YAP1 Promotes Osteoporotic Mice Bone Defect Repair via the Activating of Wnt Signaling Pathway,” Cellular Signalling 116 (2024): 111037, https://doi.org/10.1016/j.cellsig.2024.111037.

[43] L. Xiong, H. H. Guo, J. X. Pan, et al., “ATP6AP2, a Regulator of LRP6/β-Catenin Protein Trafficking, Promotes Wnt/β-Catenin Signaling and Bone Formation in a Cell Type Dependent Manner,” Bone Research 12 (2024): 33, https://doi.org/10.1038/s41413-024-00335-7.

[44] H. Dong, Y. Cao, K. Zou, et al., “Ellagic Acid Promotes Osteoblasts Differentiation via Activating SMAD2/3 Pathway and Alleviates Bone Mass Loss in OVX Mice,” Chemico-Biological Interactions 388 (2024): 110852, https://doi.org/10.1016/j.cbi.2023.110852.

[45] J. Zhang, W. Zhang, J. Dai, X. Wang, and S. G. Shen, “Overexpression of Dlx2 Enhances Osteogenic Differentiation of BMSCs and MC3T3-E1 Cells via Direct Upregulation of Osteocalcin and Alp,” International Journal of Oral Science 11 (2019): 12, https://doi.org/10.1038/s41368-019-0046-1.

[46] J. Zheng, Y. Lu, Y. Lin, et al., “Epitranscriptomic Modifications in Mesenchymal Stem Cell Differentiation: Advances, Mechanistic Insights, and Beyond,” Cell Death and Differentiation 31 (2024): 9–27, https://doi.org/10.1038/s41418-023-01238-6.

[47] H. Zhang, R. Xu, B. Li, et al., “LncRNA NEAT1 Controls the Lineage Fates of BMSCs During Skeletal Aging by Impairing Mitochondrial Function and Pluripotency Maintenance,” Cell Death and Differentiation 29 (2022): 351–365, https://doi.org/10.1038/s41418-021-00858-0.

[48] A. V. Vashi, E. Keramidaris, K. M. Abberton, et al., “Adipose Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Using Pluronic F-127 Hydrogel In Vitro,” Biomaterials 29 (2008): 573–579, https://doi.org/10.1016/j.biomaterials.2007.10.017.

[49] Y. Yao, Z. Bi, R. Wu, et al., “METTL3 Inhibits BMSC Adipogenic Differentiation by Targeting the JAK1/STAT5/C/EBPβ Pathway via an m(6)A-YTHDF2-Dependent Manner,” FASEB Journal 33 (2019): 7529–7544, https://doi.org/10.1096/fj.201802644R.

[50] C. H. Chiang, Y. C. Kao, Y. H. Lin, et al., “Reactive Oxygen Species Regulate Adipose-Osteogenic Lineage Commitment of Human Mesenchymal Stem Cells by Modulating Gene Expression of C/EBP Homology Protein and Aldo-Keto Reductase Family 1 Member A1,” Cell & Bioscience 15 (2025): 104, https://doi.org/10.1186/s13578-025-01448-0.

[51] M. Tencerova, E. Rendina-Ruedy, D. Neess, et al., “Metabolic Programming Determines the Lineage-Differentiation Fate of Murine Bone Marrow Stromal Progenitor Cells,” Bone Research 7 (2019): 35, https://doi.org/10.1038/s41413-019-0076-5.

[52] M. Cao, Q. Pan, H. Dong, et al., “Adipose-Derived Mesenchymal Stem Cells Improve Glucose Homeostasis in High-Fat Diet-Induced Obese Mice,” Stem Cell Research & Therapy 6 (2015): 208, https://doi.org/10.1186/s13287-015-0201-3.

[53] J. H. Choi, J. M. Gimble, K. Lee, et al., “Adipose Tissue Engineering for Soft Tissue Regeneration,” Tissue Engineering, Part B, Reviews 16 (2010): 413–426, https://doi.org/10.1089/ten.TEB.2009.0544.

[54] Y. S. Choi, S. N. Park, and H. Suh, “Adipose Tissue Engineering Using Mesenchymal Stem Cells Attached to Injectable PLGA Spheres,” Biomaterials 26 (2005): 5855–5863, https://doi.org/10.1016/j.biomaterials.2005.02.022.

[55] P. Deng, Q. Yuan, Y. Cheng, et al., “Loss of KDM4B Exacerbates Bone-Fat Imbalance and Mesenchymal Stromal Cell Exhaustion in Skeletal Aging,” Cell Stem Cell 28 (2021): 1057–1073.e1057, https://doi.org/10.1016/j.stem.2021.01.010.

[56] T. H. Ambrosi, A. Scialdone, A. Graja, et al., “Adipocyte Accumulation in the Bone Marrow During Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration,” Cell Stem Cell 20 (2017): 771–784.e776, https://doi.org/10.1016/j.stem.2017.02.009.

[57] B. Yu, L. Huo, Y. Liu, et al., “PGC-1α Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ,” Cell Stem Cell 23 (2018): 193–209.e195, https://doi.org/10.1016/j.stem.2018.06.009.

[58] M. N. Wosczyna, E. E. Perez Carbajal, M. W. Wagner, et al., “Targeting microRNA-Mediated Gene Repression Limits Adipogenic Conversion of Skeletal Muscle Mesenchymal Stromal Cells,” Cell Stem Cell 28 (2021): 1323–1334.e1328, https://doi.org/10.1016/j.stem.2021.04.008.

[59] J. H. Hong, E. S. Hwang, M. McManus, et al., “TAZ, a Transcriptional Modulator of Mesenchymal Stem Cell Differentiation,” Science 309 (2005): 1074–1078, https://doi.org/10.1126/science.1110955.

[60] J. Meng, J. Lu, C. Jiang, et al., “Collagen Hydrogel-Driven Pyroptosis Suppression and Combined Microfracture Technique Delay Osteoarthritis Progression,” Biomaterials 314 (2025): 122817, https://doi.org/10.1016/j.biomaterials.2024.122817.

[61] D. Liu, X. Wang, C. Gao, et al., “Biodegradable Piezoelectric-Conductive Integrated Hydrogel Scaffold for Repair of Osteochondral Defects,” Advanced Materials 36 (2024): e2409400, https://doi.org/10.1002/adma.202409400.

[62] T. Sun, Z. Feng, W. He, et al., “Novel 3D-Printing Bilayer GelMA-Based Hydrogel Containing BP,β-TCP and Exosomes for Cartilage-Bone Integrated Repair,” Biofabrication 16 (2023): 015008, https://doi.org/10.1088/1758-5090/ad04fe.

[63] S. H. Cui, Y. Yan, A. Lu, et al., “Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment,” ACS Nano 18 (2024): 8125–8142, https://doi.org/10.1021/acsnano.3c11848.

[64] M. O. Freire and T. E. Van Dyke, “Natural Resolution of Inflammation,” Periodontology 2000 63 (2013): 149–164, https://doi.org/10.1111/prd.12034.

[65] Y. Shi, Y. Wang, Q. Li, K. Liu, J. Hou, and C. Shao, “Immunoregulatory Mechanisms of Mesenchymal Stem and Stromal Cells in Inflammatory Diseases,” Nature Reviews. Nephrology 14 (2018): 493–507, https://doi.org/10.1038/s41581-018-0023-5.

[66] P. Li, Q. Ou, S. Shi, and C. Shao, “Immunomodulatory Properties of Mesenchymal Stem Cells/Dental Stem Cells and Their Therapeutic Applications,” Cellular & Molecular Immunology 20 (2023): 558–569, https://doi.org/10.1038/s41423-023-00998-y.

[67] M. E. Castro-Manrreza and J. J. Montesinos, “Immunoregulation by Mesenchymal Stem Cells: Biological Aspects and Clinical Applications,” Journal of Immunology Research 2015 (2015): 394917, https://doi.org/10.1155/2015/394917.

[68] F. Gu, K. Zhang, J. Li, et al., “Changes of Migration, Immunoregulation and Osteogenic Differentiation of Mesenchymal Stem Cells in Different Stages of Inflammation,” International Journal of Medical Sciences 19 (2022): 25–33, https://doi.org/10.7150/ijms.58428.

[69] M. Li, H. Yin, Z. Yan, et al., “The Immune Microenvironment in Cartilage Injury and Repair,” Acta Biomaterialia 140 (2022): 23–42, https://doi.org/10.1016/j.actbio.2021.12.006.

[70] S. Aggarwal and M. F. Pittenger, “Human Mesenchymal Stem Cells Modulate Allogeneic Immune Cell Responses,” Blood 105 (2005): 1815–1822, https://doi.org/10.1182/blood-2004-04-1559.

[71] X. X. Jiang, Y. Zhang, B. Liu, et al., “Human Mesenchymal Stem Cells Inhibit Differentiation and Function of Monocyte-Derived Dendritic Cells,” Blood 105 (2005): 4120–4126, https://doi.org/10.1182/blood-2004-02-0586.

[72] B. J. Warn-Cramer, G. T. Cottrell, J. M. Burt, and A. F. Lau, “Regulation of Connexin-43 Gap Junctional Intercellular Communication by Mitogen-Activated Protein Kinase,” Journal of Biological Chemistry 273 (1998): 9188–9196, https://doi.org/10.1074/jbc.273.15.9188.

[73] A. Schajnovitz, T. Itkin, G. D'Uva, et al., “CXCL12 Secretion by Bone Marrow Stromal Cells Is Dependent on Cell Contact and Mediated by Connexin-43 and Connexin-45 Gap Junctions,” Nature Immunology 12 (2011): 391–398, https://doi.org/10.1038/ni.2017.

[74] A. Naji, B. Favier, F. Deschaseaux, N. Rouas-Freiss, M. Eitoku, and N. Suganuma, “Mesenchymal Stem/Stromal Cell Function in Modulating Cell Death,” Stem Cell Research & Therapy 10 (2019): 56, https://doi.org/10.1186/s13287-019-1158-4.

[75] G. M. Spaggiari, A. Capobianco, H. Abdelrazik, F. Becchetti, M. C. Mingari, and L. Moretta, “Mesenchymal Stem Cells Inhibit Natural Killer-Cell Proliferation, Cytotoxicity, and Cytokine Production: Role of Indoleamine 2,3-Dioxygenase and Prostaglandin E2,” Blood 111 (2008): 1327–1333, https://doi.org/10.1182/blood-2007-02-074997.

[76] A. R. R. Weiss and M. H. Dahlke, “Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs,” Frontiers in Immunology 10 (2019): 1191, https://doi.org/10.3389/fimmu.2019.01191.

[77] P. Luz-Crawford, F. Djouad, K. Toupet, et al., “Mesenchymal Stem Cell-Derived Interleukin 1 Receptor Antagonist Promotes Macrophage Polarization and Inhibits B Cell Differentiation,” Stem Cells 34 (2016): 483–492, https://doi.org/10.1002/stem.2254.

[78] R. F. Loeser, J. A. Collins, and B. O. Diekman, “Ageing and the Pathogenesis of Osteoarthritis,” Nature Reviews Rheumatology 12 (2016): 412–420, https://doi.org/10.1038/nrrheum.2016.65.

[79] M. V. Thomas and D. A. Puleo, “Infection, Inflammation, and Bone Regeneration: A Paradoxical Relationship,” Journal of Dental Research 90 (2011): 1052–1061, https://doi.org/10.1177/0022034510393967.

[80] K. Suzuki, “Chronic Inflammation as an Immunological Abnormality and Effectiveness of Exercise,” Biomolecules 9 (2019): 223, https://doi.org/10.3390/biom9060223.

[81] J. M. Karp and G. S. Leng Teo, “Mesenchymal Stem Cell Homing: The Devil Is in the Details,” Cell Stem Cell 4 (2009): 206–216, https://doi.org/10.1016/j.stem.2009.02.001.

[82] M. Honczarenko, Y. le, M. Swierkowski, I. Ghiran, A. M. Glodek, and L. E. Silberstein, “Human Bone Marrow Stromal Cells Express a Distinct Set of Biologically Functional Chemokine Receptors,” Stem Cells 24 (2006): 1030–1041, https://doi.org/10.1634/stemcells.2005-0319.

[83] R. Szydlak, “Biological, Chemical and Mechanical Factors Regulating Migration and Homing of Mesenchymal Stem Cells,” World Journal of Stem Cells 13 (2021): 619–631, https://doi.org/10.4252/wjsc.v13.i6.619.

[84] M. Salvadori, N. Cesari, A. Murgia, P. Puccini, B. Riccardi, and M. Dominici, “Dissecting the Pharmacodynamics and Pharmacokinetics of MSCs to Overcome Limitations in Their Clinical Translation,” Molecular Therapy – Methods & Clinical Development 14 (2019): 1–15, https://doi.org/10.1016/j.omtm.2019.05.004.

[85] N. Ono and H. M. Kronenberg, “Bone Repair and Stem Cells,” Current Opinion in Genetics & Development 40 (2016): 103–107, https://doi.org/10.1016/j.gde.2016.06.012.

[86] K. Mizuhashi, W. Ono, Y. Matsushita, et al., “Resting Zone of the Growth Plate Houses a Unique Class of Skeletal Stem Cells,” Nature 563 (2018): 254–258, https://doi.org/10.1038/s41586-018-0662-5.

[87] C. T. J. van Velthoven and T. A. Rando, “Stem Cell Quiescence: Dynamism, Restraint, and Cellular Idling,” Cell Stem Cell 24 (2019): 213–225, https://doi.org/10.1016/j.stem.2019.01.001.

[88] D. Saul and S. Khosla, “Fracture Healing in the Setting of Endocrine Diseases, Aging, and Cellular Senescence,” Endocrine Reviews 43 (2022): 984–1002, https://doi.org/10.1210/endrev/bnac008.

[89] H. S. Shu, Y. L. Liu, X. T. Tang, et al., “Tracing the Skeletal Progenitor Transition During Postnatal Bone Formation,” Cell Stem Cell 28 (2021): 2122–2136.e2123, https://doi.org/10.1016/j.stem.2021.08.010.

[90] J. Liang, J. Wang, B. Sui, et al., “Ptip Safeguards the Epigenetic Control of Skeletal Stem Cell Quiescence and Potency in Skeletogenesis,” Science Bulletin (Beijing) 69 (2024): 2099–2113, https://doi.org/10.1016/j.scib.2024.02.036.

[91] S. Zhou, Q. Dai, X. Huang, et al., “STAT3 Is Critical for Skeletal Development and Bone Homeostasis by Regulating Osteogenesis,” Nature Communications 12 (2021): 6891, https://doi.org/10.1038/s41467-021-27273-w.

[92] M. Hadjiargyrou and R. J. O'Keefe, “The Convergence of Fracture Repair and Stem Cells: Interplay of Genes, Aging, Environmental Factors and Disease,” Journal of Bone and Mineral Research 29 (2014): 2307–2322, https://doi.org/10.1002/jbmr.2373.

[93] B. L. Riggs, “The Mechanisms of Estrogen Regulation of Bone Resorption,” Journal of Clinical Investigation 106 (2000): 1203–1204, https://doi.org/10.1172/jci11468.

[94] L. Zhang, Y. L. Zheng, R. Wang, X. Q. Wang, and H. Zhang, “Exercise for Osteoporosis: A Literature Review of Pathology and Mechanism,” Frontiers in Immunology 13 (2022): 1005665, https://doi.org/10.3389/fimmu.2022.1005665.

[95] H. Takayanagi, “Osteoimmunology: Shared Mechanisms and Crosstalk Between the Immune and Bone Systems,” Nature Reviews. Immunology 7 (2007): 292–304, https://doi.org/10.1038/nri2062.

[96] J. H. Kim, X. Liu, J. Wang, et al., “Wnt Signaling in Bone Formation and Its Therapeutic Potential for Bone Diseases,” Therapeutic Advances in Musculoskeletal Disease 5 (2013): 13–31, https://doi.org/10.1177/1759720x12466608.

[97] G. Huang, W. Yin, X. Zhao, et al., “Osteoking Inhibits Apoptosis of BMSCs in Osteoporotic Rats via PI3K/AKT Signaling Pathway,” Journal of Ethnopharmacology 340 (2025): 118961, https://doi.org/10.1016/j.jep.2024.118961.

[98] Q. Yang, Y. Zou, X. Wei, et al., “PTP1B Knockdown Alleviates BMSCs Senescence via Activating AMPK-Mediated Mitophagy and Promotes Osteogenesis in Senile Osteoporosis,” Biochimica et Biophysica Acta – Molecular Basis of Disease 1869 (2023): 166795, https://doi.org/10.1016/j.bbadis.2023.166795.

[99] Q. He, Z. Liu, X. Xia, et al., “Amlexanox Enforces Osteogenic Differentiation and Bone Homeostasis Through Inhibiting Ubiquitin-Dependent Degradation of β-Catenin,” International Journal of Biological Sciences 20 (2024): 5254–5271, https://doi.org/10.7150/ijbs.101507.

[100] Z. Luo, W. Wei, D. Qiu, et al., “Rejuvenation of BMSCs Senescence by Pharmacological Enhancement of TFEB-Mediated Autophagy Alleviates Aged-Related Bone Loss and Extends Lifespan in Middle Aged Mice,” Bone Research 12 (2024): 45, https://doi.org/10.1038/s41413-024-00351-7.

[101] F. Liu, Y. Yuan, L. Bai, et al., “LRRc17 Controls BMSC Senescence via Mitophagy and Inhibits the Therapeutic Effect of BMSCs on Ovariectomy-Induced Bone Loss,” Redox Biology 43 (2021): 101963, https://doi.org/10.1016/j.redox.2021.101963.

[102] Z. Ding, G. Ma, B. Zhou, et al., “Targeting miR-29 Mitigates Skeletal Senescence and Bolsters Therapeutic Potential of Mesenchymal Stromal Cells,” Cell Reports Medicine 5 (2024): 101665, https://doi.org/10.1016/j.xcrm.2024.101665.

[103] X. Li, J. Xu, B. Dai, X. Wang, Q. Guo, and L. Qin, “Targeting Autophagy in Osteoporosis: From Pathophysiology to Potential Therapy,” Ageing Research Reviews 62 (2020): 101098, https://doi.org/10.1016/j.arr.2020.101098.

[104] X. Feng and S. L. Teitelbaum, “Osteoclasts: New Insights,” Bone Research 1 (2013): 11–26, https://doi.org/10.4248/br201301003.

[105] Y. Zhou, Y. Yamamoto, Z. Xiao, and T. Ochiya, “The Immunomodulatory Functions of Mesenchymal Stromal/Stem Cells Mediated via Paracrine Activity,” Journal of Clinical Medicine 8 (2019): 1025.

[106] S. Yin, S. Lin, J. Xu, G. Yang, H. Chen, and X. Jiang, “Dominoes With Interlocking Consequences Triggered by Zinc: Involvement of Microelement-Stimulated MSC-Derived Exosomes in Senile Osteogenesis and Osteoclast Dialogue,” Journal of Nanobiotechnology 21 (2023): 346, https://doi.org/10.1186/s12951-023-02085-w.

[107] Y. Zhang, J. Bai, B. Xiao, and C. Li, “BMSC-Derived Exosomes Promote Osteoporosis Alleviation via M2 Macrophage Polarization,” Molecular Medicine 30 (2024): 220, https://doi.org/10.1186/s10020-024-00904-w.

[108] G. D. Lu, P. Cheng, T. Liu, and Z. Wang, “BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis,” Frontiers in Cell and Development Biology 8 (2020): 608521, https://doi.org/10.3389/fcell.2020.608521.

[109] W. Kuang, L. Zheng, X. Xu, et al., “Dysregulation of the miR-146a-Smad4 Axis Impairs Osteogenesis of Bone Mesenchymal Stem Cells Under Inflammation,” Bone Research 5 (2017): 17037, https://doi.org/10.1038/boneres.2017.37.

[110] H. Shen, W. Jiang, Y. Yu, et al., “microRNA-146a Mediates Distraction Osteogenesis via Bone Mesenchymal Stem Cell Inflammatory Response,” Acta Histochemica 124 (2022): 151913, https://doi.org/10.1016/j.acthis.2022.151913.

[111] J. Chen, J. Chen, J. Chen, et al., “Pretreated Exosomes by Electrical Stimulation Accelerate Bone Regeneration,” Bioactive Materials 51 (2025): 383–398, https://doi.org/10.1016/j.bioactmat.2025.04.019.

[112] Y. Wang, L. Sun, Z. Dong, et al., “Targeted Inhibition of Ferroptosis in Bone Marrow Mesenchymal Stem Cells by Engineered Exosomes Alleviates Bone Loss in Smoking-Related Osteoporosis,” Materials Today Bio 31 (2025): 101501, https://doi.org/10.1016/j.mtbio.2025.101501.

[113] L. J. Crofford, “Use of NSAIDs in Treating Patients With Arthritis,” Arthritis Research & Therapy 15, no. 3 (2013): S2, https://doi.org/10.1186/ar4174.

[114] J. A. Buckwalter and J. A. Martin, “Osteoarthritis,” Advanced Drug Delivery Reviews 58 (2006): 150–167, https://doi.org/10.1016/j.addr.2006.01.006.

[115] Y. Cho, S. Jeong, H. Kim, et al., “Disease-Modifying Therapeutic Strategies in Osteoarthritis: Current Status and Future Directions,” Experimental & Molecular Medicine 53 (2021): 1689–1696, https://doi.org/10.1038/s12276-021-00710-y.

[116] K. Song, J. Hu, M. Yang, et al., “Pulsed Electromagnetic Fields Potentiate Bone Marrow Mesenchymal Stem Cell Chondrogenesis by Regulating the Wnt/β-Catenin Signaling Pathway,” Journal of Translational Medicine 22 (2024): 741, https://doi.org/10.1186/s12967-024-05470-7.

[117] L. Feng, Z. M. Yang, Y. C. Li, et al., “Linc-ROR Promotes Mesenchymal Stem Cells Chondrogenesis and Cartilage Formation via Regulating SOX9 Expression,” Osteoarthritis and Cartilage 29 (2021): 568–578, https://doi.org/10.1016/j.joca.2020.12.020.

[118] L. Yang, Z. Ren, S. Yan, et al., “Nsun4 and Mettl3 Mediated Translational Reprogramming of Sox9 Promotes BMSC Chondrogenic Differentiation,” Communications Biology 5 (2022): 495, https://doi.org/10.1038/s42003-022-03420-x.

[119] X. Sun, Z. Ma, X. Zhao, et al., “Three-Dimensional Bioprinting of Multicell-Laden Scaffolds Containing Bone Morphogenic Protein-4 for Promoting M2 Macrophage Polarization and Accelerating Bone Defect Repair in Diabetes Mellitus,” Bioactive Materials 6 (2021): 757–769, https://doi.org/10.1016/j.bioactmat.2020.08.030.

[120] K. Ma, B. Zhu, Z. Wang, et al., “Articular Chondrocyte-Derived Extracellular Vesicles Promote Cartilage Differentiation of Human Umbilical Cord Mesenchymal Stem Cells by Activation of Autophagy,” Journal of Nanobiotechnology 18 (2020): 163, https://doi.org/10.1186/s12951-020-00708-0.

[121] L. He, T. He, J. Xing, et al., “Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Protect Cartilage Damage and Relieve Knee Osteoarthritis Pain in a Rat Model of Osteoarthritis,” Stem Cell Research & Therapy 11 (2020): 276, https://doi.org/10.1186/s13287-020-01781-w.

[122] H. Zhang, W. Yan, J. Wang, et al., “Surface Functionalization of Exosomes for Chondrocyte-Targeted siRNA Delivery and Cartilage Regeneration,” Journal of Controlled Release 369 (2024): 493–505, https://doi.org/10.1016/j.jconrel.2024.04.009.

[123] W. Lou, X. Qiu, Y. Qin, Y. Lu, Y. Cao, and H. Lu, “3D-Printed Advanced Scaffold Armed With Exosomes Derived From Human Skeletal Stem Cell Identified by Single-Cell RNA Sequencing Enhances Osteochondral Regeneration,” Bioactive Materials 51 (2025): 231–256, https://doi.org/10.1016/j.bioactmat.2025.04.028.

[124] C. Tu, X. Gao, H. Zheng, et al., “Innovative Injectable, Self-Healing, Exosome Cross-Linked Biomimetic Hydrogel for Cartilage Regeneration,” Journal of Controlled Release 381 (2025): 113608, https://doi.org/10.1016/j.jconrel.2025.113608.

[125] M. Wang, Y. Wu, G. Li, et al., “Articular Cartilage Repair Biomaterials: Strategies and Applications,” Materials Today Bio 24 (2024): 100948, https://doi.org/10.1016/j.mtbio.2024.100948.

[126] L. Shang, B. Ma, F. Wang, et al., “Nanotextured Silk Fibroin/Hydroxyapatite Biomimetic Bilayer Tough Structure Regulated Osteogenic/Chondrogenic Differentiation of Mesenchymal Stem Cells for Osteochondral Repair,” Cell Proliferation 53 (2020): e12917, https://doi.org/10.1111/cpr.12917.

[127] K. H. Molitoris, M. Huang, and G. S. Baht, “Osteoimmunology of Fracture Healing,” Current Osteoporosis Reports 22 (2024): 330–339, https://doi.org/10.1007/s11914-024-00869-z.

[128] B. Ganse, M. Orth, M. Roland, et al., “Concepts and Clinical Aspects of Active Implants for the Treatment of Bone Fractures,” Acta Biomaterialia 146 (2022): 1–9, https://doi.org/10.1016/j.actbio.2022.05.001.

[129] J. Pajarinen, T. Lin, E. Gibon, et al., “Mesenchymal Stem Cell-Macrophage Crosstalk and Bone Healing,” Biomaterials 196 (2019): 80–89, https://doi.org/10.1016/j.biomaterials.2017.12.025.

[130] M. G. Bixel, K. K. Sivaraj, M. Timmen, et al., “Angiogenesis Is Uncoupled From Osteogenesis During Calvarial Bone Regeneration,” Nature Communications 15 (2024): 4575, https://doi.org/10.1038/s41467-024-48579-5.

[131] F. Xing, Z. Chi, R. Yang, et al., “Chitin-Hydroxyapatite-Collagen Composite Scaffolds for Bone Regeneration,” International Journal of Biological Macromolecules 184 (2021): 170–180, https://doi.org/10.1016/j.ijbiomac.2021.05.019.

[132] D. Wu, X. Chang, J. Tian, et al., “Bone Mesenchymal Stem Cells Stimulation by Magnetic Nanoparticles and a Static Magnetic Field: Release of Exosomal miR-1260a Improves Osteogenesis and Angiogenesis,” Journal of Nanobiotechnology 19 (2021): 209, https://doi.org/10.1186/s12951-021-00958-6.

[133] C. Cui, Y. Zhao, J. Yan, et al., “Peptide Platform for 3D-Printed Ti Implants With Synergistic Antibacterial and Osteogenic Functions to Enhance Osseointegration,” Materials Today Bio 30 (2025): 101430, https://doi.org/10.1016/j.mtbio.2024.101430.

[134] R. Hang, Y. Zhao, H. Chen, et al., “Construction and High-Throughput Screening of Gradient Nanowire Coatings on Titanium Surface Towards Ameliorated Osseointegration,” Materials Today Bio 30 (2025): 101392, https://doi.org/10.1016/j.mtbio.2024.101392.

[135] Z. Wen, S. Li, Y. Liu, et al., “An Engineered M2 Macrophage-Derived Exosomes-Loaded Electrospun Biomimetic Periosteum Promotes Cell Recruitment, Immunoregulation, and Angiogenesis in Bone Regeneration,” Bioactive Materials 50 (2025): 95–115, https://doi.org/10.1016/j.bioactmat.2025.03.027.

[136] S. L. Ruggiero, T. B. Dodson, J. Fantasia, et al., “American Association of Oral and Maxillofacial Surgeons Position Paper on Medication-Related Osteonecrosis of the Jaw—2014 Update,” Journal of Oral and Maxillofacial Surgery 72 (2014): 1938–1956, https://doi.org/10.1016/j.joms.2014.04.031.

[137] P. J. Voss, A. Matsumoto, E. Alvarado, R. Schmelzeisen, F. Duttenhöfer, and P. Poxleitner, “Treatment of Stage II Medication-Related Osteonecrosis of the Jaw With Necrosectomy and Autologous Bone Marrow Mesenchymal Stem Cells,” Odontology 105 (2017): 484–493, https://doi.org/10.1007/s10266-017-0295-4.

[138] K. Ogata, M. Matsumura, M. Moriyama, W. Katagiri, H. Hibi, and S. Nakamura, “Cytokine Mixtures Mimicking Secretomes From Mesenchymal Stem Cells Improve Medication-Related Osteonecrosis of the Jaw in a Rat Model,” JBMR Plus 2 (2018): 69–80, https://doi.org/10.1002/jbm4.10013.

[139] Y. Matsuura, I. Atsuta, Y. Ayukawa, et al., “Therapeutic Interactions Between Mesenchymal Stem Cells for Healing Medication-Related Osteonecrosis of the Jaw,” Stem Cell Research & Therapy 7 (2016): 119, https://doi.org/10.1186/s13287-016-0367-3.

[140] M. Mazreku, L. u. Danišovič, M. Klein, and M. Kleinová, “Recent Stem-Cell-Based and Stem-Cell-Free Possibilities for the Therapeutic Management of the Osteonecrosis of the Jaw,” Biomolecules 15 (2025): 595.

[141] F. J. Rodríguez-Lozano, R. Oñate-Sánchez, M. Gonzálvez-García, et al., “Allogeneic Bone Marrow Mesenchymal Stem Cell Transplantation in Tooth Extractions Sites Ameliorates the Incidence of Osteonecrotic Jaw-Like Lesions in Zoledronic Acid-Treated Rats,” Journal of Clinical Medicine 9 (2020): 1649.

[142] N. Sayed, P. Allawadhi, A. Khurana, et al., “Gene Therapy: Comprehensive Overview and Therapeutic Applications,” Life Sciences 294 (2022): 120375, https://doi.org/10.1016/j.lfs.2022.120375.

[143] C. Li, Y. du, T. Zhang, et al., ““Genetic Scissors” CRISPR/Cas9 Genome Editing Cutting-Edge Biocarrier Technology for Bone and Cartilage Repair,” Bioactive Materials 22 (2023): 254–273, https://doi.org/10.1016/j.bioactmat.2022.09.026.

[144] H. Li, Y. Yang, W. Hong, M. Huang, M. Wu, and X. Zhao, “Applications of Genome Editing Technology in the Targeted Therapy of Human Diseases: Mechanisms, Advances and Prospects,” Signal Transduction and Targeted Therapy 5 (2020): 1, https://doi.org/10.1038/s41392-019-0089-y.

[145] A. Hazrati, K. Malekpour, S. Soudi, and S. M. Hashemi, “CRISPR/Cas9-Engineered Mesenchymal Stromal/Stem Cells and Their Extracellular Vesicles: A New Approach to Overcoming Cell Therapy Limitations,” Biomedicine & Pharmacotherapy 156 (2022): 113943, https://doi.org/10.1016/j.biopha.2022.113943.

[146] S. Arandjelovic, J. S. A. Perry, M. Zhou, et al., “ELMO1 Signaling Is a Promoter of Osteoclast Function and Bone Loss,” Nature Communications 12 (2021): 4974, https://doi.org/10.1038/s41467-021-25239-6.

[147] G. P. Freitas, H. B. Lopes, A. T. P. Souza, et al., “Mesenchymal Stem Cells Overexpressing BMP-9 by CRISPR-Cas9 Present High In Vitro Osteogenic Potential and Enhance In Vivo Bone Formation,” Gene Therapy 28 (2021): 748–759, https://doi.org/10.1038/s41434-021-00248-8.

[148] V. A. Truong, M. N. Hsu, N. T. Kieu Nguyen, et al., “CRISPRai for Simultaneous Gene Activation and Inhibition to Promote Stem Cell Chondrogenesis and Calvarial Bone Regeneration,” Nucleic Acids Research 47 (2019): e74, https://doi.org/10.1093/nar/gkz267.

[149] X. Hu, L. Li, X. Yu, et al., “CRISPR/Cas9-Mediated Reversibly Immortalized Mouse Bone Marrow Stromal Stem Cells (BMSCs) Retain Multipotent Features of Mesenchymal Stem Cells (MSCs),” Oncotarget 8 (2017): 111847–111865, https://doi.org/10.18632/oncotarget.22915.

[150] Z. Wu, J. Zhu, Y. Wen, et al., “Hmga1-Overexpressing Lentivirus Protects Against Osteoporosis by Activating the Wnt/β-Catenin Pathway in the Osteogenic Differentiation of BMSCs,” FASEB Journal 37 (2023): e22987, https://doi.org/10.1096/fj.202300488R.

[151] Y. Guo, X. Jia, Y. Cui, et al., “Sirt3-Mediated Mitophagy Regulates AGEs-Induced BMSCs Senescence and Senile Osteoporosis,” Redox Biology 41 (2021): 101915, https://doi.org/10.1016/j.redox.2021.101915.

[152] S. Bougioukli, M. Chateau, H. Morales, et al., “Limited Potential of AAV-Mediated Gene Therapy in Transducing Human Mesenchymal Stem Cells for Bone Repair Applications,” Gene Therapy 28 (2021): 729–739, https://doi.org/10.1038/s41434-020-0182-4.

[153] X. Wang, Y. Ma, J. Chen, et al., “A Novel Decellularized Matrix of Wnt Signaling-Activated Osteocytes Accelerates the Repair of Critical-Sized Parietal Bone Defects With Osteoclastogenesis, Angiogenesis, and Neurogenesis,” Bioactive Materials 21 (2023): 110–128, https://doi.org/10.1016/j.bioactmat.2022.07.017.

[154] S. Chen, A. McCarthy, J. V. John, Y. Su, and J. Xie, “Converting 2D Nanofiber Membranes to 3D Hierarchical Assemblies With Structural and Compositional Gradients Regulates Cell Behavior,” Advanced Materials 32 (2020): e2003754, https://doi.org/10.1002/adma.202003754.

[155] J. Yang, X. Chen, T. Yuan, X. Yang, Y. Fan, and X. Zhang, “Regulation of the Secretion of Immunoregulatory Factors of Mesenchymal Stem Cells (MSCs) by Collagen-Based Scaffolds During Chondrogenesis,” Materials Science & Engineering, C: Materials for Biological Applications 70 (2017): 983–991, https://doi.org/10.1016/j.msec.2016.04.096.

[156] W. Yu, S. Li, X. Guan, et al., “Higher Yield and Enhanced Therapeutic Effects of Exosomes Derived From MSCs in Hydrogel-Assisted 3D Culture System for Bone Regeneration,” Biomaterials Advances 133 (2022): 112646, https://doi.org/10.1016/j.msec.2022.112646.

[157] Y. Della Rocca, L. Fonticoli, T. S. Rajan, et al., “Hypoxia: Molecular Pathophysiological Mechanisms in Human Diseases,” Journal of Physiology and Biochemistry 78 (2022): 739–752, https://doi.org/10.1007/s13105-022-00912-6.

[158] L. Wei, J. L. Fraser, Z.-Y. Lu, X. Hu, and S. P. Yu, “Transplantation of Hypoxia Preconditioned Bone Marrow Mesenchymal Stem Cells Enhances Angiogenesis and Neurogenesis After Cerebral Ischemia in Rats,” Neurobiology of Disease 46 (2012): 635–645, https://doi.org/10.1016/j.nbd.2012.03.002.

[159] J. Liu, H. Hao, H. Huang, et al., “Hypoxia Regulates the Therapeutic Potential of Mesenchymal Stem Cells Through Enhanced Autophagy,” International Journal of Lower Extremity Wounds 14 (2015): 63–72, https://doi.org/10.1177/1534734615573660.

[160] Y. Yang, Y. Wu, D. Yang, et al., “Secretive Derived From Hypoxia Preconditioned Mesenchymal Stem Cells Promote Cartilage Regeneration and Mitigate Joint Inflammation via Extracellular Vesicles,” Bioactive Materials 27 (2023): 98–112, https://doi.org/10.1016/j.bioactmat.2023.03.017.

[161] X. Li, Y. Jiang, X. Liu, et al., “Mesenchymal Stem Cell-Derived Apoptotic Bodies Alleviate Alveolar Bone Destruction by Regulating Osteoclast Differentiation and Function,” International Journal of Oral Science 15 (2023): 51, https://doi.org/10.1038/s41368-023-00255-y.

[162] B. Wang, H. Wen, W. Smith, D. Hao, B. He, and L. Kong, “Regulation Effects of Melatonin on Bone Marrow Mesenchymal Stem Cell Differentiation,” Journal of Cellular Physiology 234 (2019): 1008–1015, https://doi.org/10.1002/jcp.27090.

[163] F. Yang, L. Yang, Y. Li, et al., “Melatonin Protects Bone Marrow Mesenchymal Stem Cells Against Iron Overload-Induced Aberrant Differentiation and Senescence,” Journal of Pineal Research 63 (2017): e12422, https://doi.org/10.1111/jpi.12422.

[164] Y. Hu, Y. Xiong, K. Zha, et al., “Melatonin Promotes BMSCs Osteoblastic Differentiation and Relieves Inflammation by Suppressing the NF-κB Pathways,” Stem Cells International 2023 (2023): 7638842, https://doi.org/10.1155/2023/7638842.

[165] Y. Xie, N. Han, F. Li, et al., “Melatonin Enhances Osteoblastogenesis of Senescent Bone Marrow Stromal Cells Through NSD2-Mediated Chromatin Remodelling,” Clinical and Translational Medicine 12 (2022): e746, https://doi.org/10.1002/ctm2.746.

[166] J. Watanabe, M. Yamada, K. Niibe, et al., “Preconditioning of Bone Marrow-Derived Mesenchymal Stem Cells With N-Acetyl-l-Cysteine Enhances Bone Regeneration via Reinforced Resistance to Oxidative Stress,” Biomaterials 185 (2018): 25–38, https://doi.org/10.1016/j.biomaterials.2018.08.055.

[167] C. Yueyi, H. Xiaoguang, W. Jingying, et al., “Calvarial Defect Healing by Recruitment of Autogenous Osteogenic Stem Cells Using Locally Applied Simvastatin,” Biomaterials 34 (2013): 9373–9380, https://doi.org/10.1016/j.biomaterials.2013.08.060.

[168] S. Pauly, F. Luttosch, M. Morawski, N. P. Haas, G. Schmidmaier, and B. Wildemann, “Simvastatin Locally Applied From a Biodegradable Coating of Osteosynthetic Implants Improves Fracture Healing Comparable to BMP-2 Application,” Bone 45 (2009): 505–511, https://doi.org/10.1016/j.bone.2009.05.010.

[169] Y. Guo, J. Huo, D. Wu, et al., “Simvastatin Inhibits the Adipogenesis of Bone Marrow-Derived Mesenchymal Stem Cells Through the Downregulation of Chemerin/CMKLR1 Signaling,” International Journal of Molecular Medicine 46 (2020): 751–761, https://doi.org/10.3892/ijmm.2020.4606.

[170] S. C. Chuang, C. H. Chen, Y. C. Fu, et al., “Estrogen Receptor Mediates Simvastatin-Stimulated Osteogenic Effects in Bone Marrow Mesenchymal Stem Cells,” Biochemical Pharmacology 98 (2015): 453–464, https://doi.org/10.1016/j.bcp.2015.09.018.

[171] Y. Wang, L. Che, X. Chen, et al., “Repurpose Dasatinib and Quercetin: Targeting Senescent Cells Ameliorates Postmenopausal Osteoporosis and Rejuvenates Bone Regeneration,” Bioactive Materials 25 (2023): 13–28, https://doi.org/10.1016/j.bioactmat.2023.01.009.

[172] S. Srivastava, R. Bankar, and P. Roy, “Assessment of the Role of Flavonoids for Inducing Osteoblast Differentiation in Isolated Mouse Bone Marrow Derived Mesenchymal Stem Cells,” Phytomedicine 20 (2013): 683–690, https://doi.org/10.1016/j.phymed.2013.03.001.

[173] L. Bai, Y. Liu, X. Zhang, et al., “Osteoporosis Remission via an Anti-Inflammaging Effect by Icariin Activated Autophagy,” Biomaterials 297 (2023): 122125, https://doi.org/10.1016/j.biomaterials.2023.122125.

[174] K. I. Kim, S. Park, and G. I. Im, “Osteogenic Differentiation and Angiogenesis With Cocultured Adipose-Derived Stromal Cells and Bone Marrow Stromal Cells,” Biomaterials 35 (2014): 4792–4804, https://doi.org/10.1016/j.biomaterials.2014.02.048.

[175] Y. Wang, W. Li, Y. Guo, et al., “Mitochondria Transplantation to Bone Marrow Stromal Cells Promotes Angiogenesis During Bone Repair,” Advanced Science (Weinheim) 11 (2024): e2403201, https://doi.org/10.1002/advs.202403201.

[176] W. Cai, J. Zhang, Y. Yu, et al., “Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis,” Advanced Science (Weinheim) 10 (2023): e2204871, https://doi.org/10.1002/advs.202204871.

[177] H. Xiong, H. Qiu, C. Wang, et al., “Melatonin-Loaded Bioactive Microspheres Accelerate Aged Bone Regeneration by Formation of Tunneling Nanotubes to Enhance Mitochondrial Transfer,” Materials Today Bio 28 (2024): 101175, https://doi.org/10.1016/j.mtbio.2024.101175.

[178] A. C. Court, A. M. Vega-Letter, E. Parra-Crisóstomo, et al., “Mitochondrial Transfer Balances Cell Redox, Energy and Metabolic Homeostasis in the Osteoarthritic Chondrocyte Preserving Cartilage Integrity,” Theranostics 14 (2024): 6471–6486, https://doi.org/10.7150/thno.96723.

[179] M. Mahrouf-Yorgov, L. Augeul, C. C. Da Silva, et al., “Mesenchymal Stem Cells Sense Mitochondria Released From Damaged Cells as Danger Signals to Activate Their Rescue Properties,” Cell Death and Differentiation 24 (2017): 1224–1238, https://doi.org/10.1038/cdd.2017.51.

[180] S. Qiu, L. Cao, D. Xiang, et al., “Enhanced Osteogenic Differentiation in 3D Hydrogel Scaffold via Macrophage Mitochondrial Transfer,” Journal of Nanobiotechnology 22 (2024): 540, https://doi.org/10.1186/s12951-024-02757-1.

[181] C. Liu, Q. Yu, Z. Yuan, et al., “Engineering the Viscoelasticity of Gelatin Methacryloyl (GelMA) Hydrogels via Small “Dynamic Bridges” to Regulate BMSC Behaviors for Osteochondral Regeneration,” Bioactive Materials 25 (2023): 445–459, https://doi.org/10.1016/j.bioactmat.2022.07.031.

[182] J. Wang, Y. Wu, G. Li, et al., “Engineering Large-Scale Self-Mineralizing Bone Organoids With Bone Matrix-Inspired Hydroxyapatite Hybrid Bioinks,” Advanced Materials 36 (2024): e2309875, https://doi.org/10.1002/adma.202309875.

[183] J. A. Maresca, D. C. DeMel, G. A. Wagner, C. Haase, and J. P. Geibel, “Three-Dimensional Bioprinting Applications for Bone Tissue Engineering,” Cells 12 (2023): 1230, https://doi.org/10.3390/cells12091230.

[184] Y. Wang, J. Wang, R. Gao, et al., “Biomimetic Glycopeptide Hydrogel Coated PCL/nHA Scaffold for Enhanced Cranial Bone Regeneration via Macrophage M2 Polarization-Induced Osteo-Immunomodulation,” Biomaterials 285 (2022): 121538, https://doi.org/10.1016/j.biomaterials.2022.121538.

[185] Y. Liu, C. Shi, P. Ming, et al., “Biomimetic Fabrication of Sr-Silk Fibroin Co-Assembly Hydroxyapatite Based Microspheres With Angiogenic and Osteogenic Properties for Bone Tissue Engineering,” Materials Today Bio 25 (2024): 101011, https://doi.org/10.1016/j.mtbio.2024.101011.

[186] P. Ming, Y. Liu, P. Yu, et al., “A Biomimetic se-nHA/PC Composite Microsphere With Synergistic Immunomodulatory and Osteogenic Ability to Activate Bone Regeneration in Periodontitis,” Small 20 (2024): e2305490, https://doi.org/10.1002/smll.202305490.

[187] P. Ming, B. Li, Q. Li, et al., “Multifunctional Sericin-Based Biomineralized Nanoplatforms With Immunomodulatory and Angio/Osteo-Genic Activity for Accelerated Bone Regeneration in Periodontitis,” Biomaterials 314 (2025): 122885, https://doi.org/10.1016/j.biomaterials.2024.122885.

[188] X. Zhang, Y. Xia, J. Xu, et al., “Cell-Free Chitosan/Silk Fibroin/Bioactive Glass Scaffolds With Radial Pore for In Situ Inductive Regeneration of Critical-Size Bone Defects,” Carbohydrate Polymers 332 (2024): 121945, https://doi.org/10.1016/j.carbpol.2024.121945.

[189] H. Lin, Z. Li, Z. Xie, et al., “An Anti-Infection and Biodegradable TFRD-Loaded Porous Scaffold Promotes Bone Regeneration in Segmental Bone Defects: Experimental Studies,” International Journal of Surgery 110 (2024): 3269–3284, https://doi.org/10.1097/js9.0000000000001291.

[190] P. Bhattacharjee, B. Kundu, D. Naskar, et al., “Silk Scaffolds in Bone Tissue Engineering: An Overview,” Acta Biomaterialia 63 (2017): 1–17, https://doi.org/10.1016/j.actbio.2017.09.027.

[191] F. Tao, Y. Cheng, X. Shi, et al., “Applications of Chitin and Chitosan Nanofibers in Bone Regenerative Engineering,” Carbohydrate Polymers 230 (2020): 115658, https://doi.org/10.1016/j.carbpol.2019.115658.

[192] J. Li, G. Wei, G. Liu, et al., “Regulating Type H Vessel Formation and Bone Metabolism via Bone-Targeting Oral Micro/Nano-Hydrogel Microspheres to Prevent Bone Loss,” Advanced Science (Weinheim) 10 (2023): e2207381, https://doi.org/10.1002/advs.202207381.

[193] C. Yan, P. Zhang, Q. Qin, et al., “3D-Printed Bone Regeneration Scaffolds Modulate Bone Metabolic Homeostasis Through Vascularization for Osteoporotic Bone Defects,” Biomaterials 311 (2024): 122699, https://doi.org/10.1016/j.biomaterials.2024.122699.

[194] I. Alonso-Fernández, H. J. Haugen, M. López-Peña, A. González-Cantalapiedra, and F. Muñoz, “Use of 3D-Printed Polylactic Acid/Bioceramic Composite Scaffolds for Bone Tissue Engineering in Preclinical In Vivo Studies: A Systematic Review,” Acta Biomaterialia 168 (2023): 1–21, https://doi.org/10.1016/j.actbio.2023.07.013.

[195] M. U. Munir, S. Salman, A. Ihsan, and T. Elsaman, “Synthesis, Characterization, Functionalization and Bio-Applications of Hydroxyapatite Nanomaterials: An Overview,” International Journal of Nanomedicine 17 (2022): 1903–1925, https://doi.org/10.2147/ijn.S360670.

[196] M. Ali, U. Farwa, S. S. Park, Y. S. Kim, and B. T. Lee, “Physico-Biological and In Vivo Evaluation of Irisin Loaded 45S5 Porous Bioglass Granules for Bone Regeneration,” Biomaterials Advances 147 (2023): 213326, https://doi.org/10.1016/j.bioadv.2023.213326.

[197] M. Sun, Y. Lu, H. Zhang, et al., “Multifunctional Composite Scaffold With Nanosilver, Graphene Oxide, and Macrophage Membrane Vesicles for Sequential Treatment of Infected Bone Defects,” Advanced Healthcare Materials 13 (2024): e2400346, https://doi.org/10.1002/adhm.202400346.

[198] D. Wang, Y. Cui, N. Yuan, et al., “Lysozyme Aggregates Functionalization of Carbon Nanotubes for Biomimetic Hydroxyapatite Mineralization,” International Journal of Biological Macromolecules 321 (2025): 145694, https://doi.org/10.1016/j.ijbiomac.2025.145694.

[199] C. Yang, K. Zhu, M. Cheng, et al., “Graphene Oxide-Decorated Microporous Sulfonated Polyetheretherketone for Guiding Osteoporotic Bone Regeneration,” Journal of Controlled Release 374 (2024): 15–27, https://doi.org/10.1016/j.jconrel.2024.07.054.

[200] V. Fitzpatrick, Z. Martín-Moldes, A. Deck, et al., “Functionalized 3D-Printed Silk-Hydroxyapatite Scaffolds for Enhanced Bone Regeneration With Innervation and Vascularization,” Biomaterials 276 (2021): 120995, https://doi.org/10.1016/j.biomaterials.2021.120995.

[201] M. Zhu, H. Zhang, Q. Zhou, et al., “Dynamic GelMA/DNA Dual-Network Hydrogels Promote Woven Bone Organoid Formation and Enhance Bone Regeneration,” Advanced Materials 37 (2025): e2501254, https://doi.org/10.1002/adma.202501254.

[202] H. Clevers, “Modeling Development and Disease With Organoids,” Cell 165 (2016): 1586–1597, https://doi.org/10.1016/j.cell.2016.05.082.

[203] L. Bai, D. Zhou, G. Li, J. Liu, X. Chen, and J. Su, “Engineering Bone/Cartilage Organoids: Strategy, Progress, and Application,” Bone Research 12 (2024): 66, https://doi.org/10.1038/s41413-024-00376-y.

[204] Z. Yang, B. Wang, W. Liu, et al., “In Situ Self-Assembled Organoid for Osteochondral Tissue Regeneration With Dual Functional Units,” Bioactive Materials 27 (2023): 200–215, https://doi.org/10.1016/j.bioactmat.2023.04.002.

[205] Q. Wang, M. Mu, W. Yu, et al., “Engineering Polyphenol-Based Osteogenic System for Bone and Cartilage Repair: Transplantation, Tissue Engineering, and Organoid,” Journal of Advanced Research (2025): S2090–1232(25)00476-X, https://doi.org/10.1016/j.jare.2025.06.067.

[206] C. Xie, R. Liang, J. Ye, et al., “High-Efficient Engineering of Osteo-Callus Organoids for Rapid Bone Regeneration Within One Month,” Biomaterials 288 (2022): 121741, https://doi.org/10.1016/j.biomaterials.2022.121741.

[207] R. Mishra, B. M. Roux, M. Posukonis, et al., “Effect of Prevascularization on In Vivo Vascularization of Poly(Propylene Fumarate)/Fibrin Scaffolds,” Biomaterials 77 (2016): 255–266, https://doi.org/10.1016/j.biomaterials.2015.10.026.

[208] X. Zhao, N. Li, Z. Zhang, et al., “Beyond Hype: Unveiling the Real Challenges in Clinical Translation of 3D Printed Bone Scaffolds and the Fresh Prospects of Bioprinted Organoids,” Journal of Nanobiotechnology 22 (2024): 500, https://doi.org/10.1186/s12951-024-02759-z.

[209] F. J. Vizoso, N. Eiro, S. Cid, J. Schneider, and R. Perez-Fernandez, “Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine,” International Journal of Molecular Sciences 18 (2017): 1852, https://doi.org/10.3390/ijms18091852.

[210] S. Rani, A. E. Ryan, M. D. Griffin, and T. Ritter, “Mesenchymal Stem Cell-Derived Extracellular Vesicles: Toward Cell-Free Therapeutic Applications,” Molecular Therapy 23 (2015): 812–823, https://doi.org/10.1038/mt.2015.44.

[211] M. Arabpour, A. Saghazadeh, and N. Rezaei, “Anti-Inflammatory and M2 Macrophage Polarization-Promoting Effect of Mesenchymal Stem Cell-Derived Exosomes,” International Immunopharmacology 97 (2021): 107823, https://doi.org/10.1016/j.intimp.2021.107823.

[212] F. Franco da Cunha, V. Andrade-Oliveira, D. Candido de Almeida, et al., “Extracellular Vesicles Isolated From Mesenchymal Stromal Cells Modulate CD4(+) T Lymphocytes Toward a Regulatory Profile,” Cells 9 (2020): 1059, https://doi.org/10.3390/cells9041059.

[213] S. Cosenza, M. Ruiz, K. Toupet, C. Jorgensen, and D. Noël, “Mesenchymal Stem Cells Derived Exosomes and Microparticles Protect Cartilage and Bone From Degradation in Osteoarthritis,” Scientific Reports 7 (2017): 16214, https://doi.org/10.1038/s41598-017-15376-8.

[214] A. Galleu, Y. Riffo-Vasquez, C. Trento, et al., “Apoptosis in Mesenchymal Stromal Cells Induces In Vivo Recipient-Mediated Immunomodulation,” Science Translational Medicine 9 (2017): eaam7828, https://doi.org/10.1126/scitranslmed.aam7828.

[215] Q. Hu, C. J. Lyon, J. K. Fletcher, W. Tang, M. Wan, and T. Y. Hu, “Extracellular Vesicle Activities Regulating Macrophage- and Tissue-Mediated Injury and Repair Responses,” Acta Pharmaceutica Sinica B 11 (2021): 1493–1512, https://doi.org/10.1016/j.apsb.2020.12.014.

[216] D. Liu, X. Kou, C. Chen, et al., “Circulating Apoptotic Bodies Maintain Mesenchymal Stem Cell Homeostasis and Ameliorate Osteopenia via Transferring Multiple Cellular Factors,” Cell Research 28 (2018): 918–933, https://doi.org/10.1038/s41422-018-0070-2.

[217] D. M. Pegtel and S. J. Gould, “Exosomes,” Annual Review of Biochemistry 88 (2019): 487–514, https://doi.org/10.1146/annurev-biochem-013118-111902.

[218] X. Yu, M. Odenthal, and J. W. Fries, “Exosomes as miRNA Carriers: Formation-Function-Future,” International Journal of Molecular Sciences 17 (2016): 2028, https://doi.org/10.3390/ijms17122028.

[219] K. Xiang, M. Hao, Z. Zhang, K. Zhang, H. Sun, and L. Zhang, “Engineering 3D-BMSC Exosome-Based Hydrogels That Collaboratively Regulate Bone Microenvironment and Promote Osteogenesis for Enhanced Cell-Free Bone Regeneration,” Materials Today Bio 32 (2025): 101881, https://doi.org/10.1016/j.mtbio.2025.101881.

[220] R. A. Haraszti, R. Miller, M. Stoppato, et al., “Exosomes Produced From 3D Cultures of MSCs by Tangential Flow Filtration Show Higher Yield and Improved Activity,” Molecular Therapy 26 (2018): 2838–2847, https://doi.org/10.1016/j.ymthe.2018.09.015.

[221] S. Y. Lee and J. W. Lee, “3D Spheroid Cultures of Stem Cells and Exosome Applications for Cartilage Repair,” Life (Basel) 12 (2022): 939, https://doi.org/10.3390/life12070939.

[222] W. Liu, L. Li, Y. Rong, et al., “Hypoxic Mesenchymal Stem Cell-Derived Exosomes Promote Bone Fracture Healing by the Transfer of miR-126,” Acta Biomaterialia 103 (2020): 196–212, https://doi.org/10.1016/j.actbio.2019.12.020.

[223] S. Ren, C. Wang, and S. Guo, “Review of the Role of Mesenchymal Stem Cells and Exosomes Derived From Mesenchymal Stem Cells in the Treatment of Orthopedic Disease,” Medical Science Monitor 28 (2022): e935937, https://doi.org/10.12659/msm.935937.

[224] Z. Weng, B. Zhang, C. Wu, et al., “Therapeutic Roles of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Cancer,” Journal of Hematology & Oncology 14 (2021): 136, https://doi.org/10.1186/s13045-021-01141-y.

[225] H. B. Koh, H. J. Kim, S. W. Kang, and T. H. Yoo, “Exosome-Based Drug Delivery: Translation From Bench to Clinic,” Pharmaceutics 15 (2023): 2042, https://doi.org/10.3390/pharmaceutics15082042.

[226] X. Zhou, B. Tang, Q. Huang, et al., “Engineered Mesenchymal Stem Cell-Derived Extracellular Vesicles Scavenge Self-Antigens for Psoriasis Therapy via Modulating Metabolic and Immunological Disorders,” Advanced Science 12 (2025): e2410067, https://doi.org/10.1002/advs.202410067.

[227] Y. Liang, L. Duan, J. Lu, and J. Xia, “Engineering Exosomes for Targeted Drug Delivery,” Theranostics 11 (2021): 3183–3195, https://doi.org/10.7150/thno.52570.

[228] S. Rayamajhi and S. Aryal, “Surface Functionalization Strategies of Extracellular Vesicles,” Journal of Materials Chemistry B 8 (2020): 4552–4569, https://doi.org/10.1039/d0tb00744g.

[229] H. Choi and D. S. Lee, “Illuminating the Physiology of Extracellular Vesicles,” Stem Cell Research & Therapy 7 (2016): 55, https://doi.org/10.1186/s13287-016-0316-1.

[230] S. Salunkhe, M. Basak, D. Chitkara, and A. Mittal, “Surface Functionalization of Exosomes for Target-Specific Delivery and In Vivo Imaging & Tracking: Strategies and Significance,” Journal of Controlled Release 326 (2020): 599–614, https://doi.org/10.1016/j.jconrel.2020.07.042.

[231] T. Ma, S. Chen, J. Wang, et al., “Enhanced Osteolysis Targeted Therapy Through Fusion of Exosomes Derived From M2 Macrophages and Bone Marrow Mesenchymal Stem Cells: Modulating Macrophage Polarization,” Small 20 (2024): e2303506, https://doi.org/10.1002/smll.202303506.

[232] D. Wang, Y. Guo, B. C. Heng, et al., “Cell Membrane Vesicles Derived From hBMSCs and hUVECs Enhance Bone Regeneration,” Bone Research 12 (2024): 23, https://doi.org/10.1038/s41413-024-00325-9.

[233] M. Zhang, W. Hu, C. Cai, Y. Wu, J. Li, and S. Dong, “Advanced Application of Stimuli-Responsive Drug Delivery System for Inflammatory Arthritis Treatment,” Materials Today Bio 14 (2022): 100223, https://doi.org/10.1016/j.mtbio.2022.100223.

[234] X. Xiong, H. Liu, Z. Zhao, et al., “DNA Aptamer-Mediated Cell Targeting,” Angewandte Chemie (International Ed. in English) 52 (2013): 1472–1476, https://doi.org/10.1002/anie.201207063.

[235] X. Liu, J. Hu, Y. Ning, et al., “Aptamer Technology and Its Applications in Bone Diseases,” Cell Transplantation 32 (2023): 9636897221144949, https://doi.org/10.1177/09636897221144949.

[236] H. W. Park, C. E. Lee, S. Kim, W. J. Jeong, and K. Kim, “Ex Vivo Peptide Decoration Strategies on Stem Cell Surfaces for Augmenting Endothelium Interaction,” Tissue Engineering. Part B, Reviews 30 (2024): 327–339, https://doi.org/10.1089/ten.TEB.2023.0210.

[237] X. Hu, Y. Wang, Y. Tan, et al., “A Difunctional Regeneration Scaffold for Knee Repair Based on Aptamer-Directed Cell Recruitment,” Advanced Materials 29 (2017): 1605235, https://doi.org/10.1002/adma.201605235.

[238] Z. Yang, T. Zhao, C. Gao, et al., “3D-Bioprinted Difunctional Scaffold for In Situ Cartilage Regeneration Based on Aptamer-Directed Cell Recruitment and Growth Factor-Enhanced Cell Chondrogenesis,” ACS Applied Materials & Interfaces 13 (2021): 23369–23383, https://doi.org/10.1021/acsami.1c01844.

[239] Y. Wang, F. Xie, Z. He, et al., “Senescence-Targeted and NAD(+)-Dependent SIRT1-Activated Nanoplatform to Counteract Stem Cell Senescence for Promoting Aged Bone Regeneration,” Small 20 (2024): e2304433, https://doi.org/10.1002/smll.202304433.

[240] F. Shams, B. Pourjabbar, N. Hashemi, et al., “Current Progress in Engineered and Nano-Engineered Mesenchymal Stem Cells for Cancer: From Mechanisms to Therapy,” Biomedicine & Pharmacotherapy 167 (2023): 115505, https://doi.org/10.1016/j.biopha.2023.115505.

[241] M. E. Hung and J. N. Leonard, “Stabilization of Exosome-Targeting Peptides via Engineered Glycosylation,” Journal of Biological Chemistry 290 (2015): 8166–8172, https://doi.org/10.1074/jbc.M114.621383.

[242] D. Schübeler, “Function and Information Content of DNA Methylation,” Nature 517 (2015): 321–326, https://doi.org/10.1038/nature14192.

[243] J. G. Letarouilly, O. Broux, and A. Clabaut, “New Insights Into the Epigenetics of Osteoporosis,” Genomics 111 (2019): 793–798, https://doi.org/10.1016/j.ygeno.2018.05.001.

[244] P. Li, C. Zhang, W. Yin, et al., “From Bone Marrow Mesenchymal Stem Cells to Diseases: The Crucial Role of m(6)A Methylation in Orthopedics,” Stem Cell Research & Therapy 16 (2025): 228, https://doi.org/10.1186/s13287-025-04364-9.

[245] A. Koch, S. C. Joosten, Z. Feng, et al., “Analysis of DNA Methylation in Cancer: Location Revisited,” Nature Reviews. Clinical Oncology 15 (2018): 459–466, https://doi.org/10.1038/s41571-018-0004-4.

[246] C. Zeng, W. Huang, Y. Li, and H. Weng, “Roles of METTL3 in Cancer: Mechanisms and Therapeutic Targeting,” Journal of Hematology & Oncology 13 (2020): 117, https://doi.org/10.1186/s13045-020-00951-w.

[247] A. L. Mattei, N. Bailly, and A. Meissner, “DNA Methylation: A Historical Perspective,” Trends in Genetics 38 (2022): 676–707, https://doi.org/10.1016/j.tig.2022.03.010.

[248] L. D. Moore, T. Le, and G. Fan, “DNA Methylation and Its Basic Function,” Neuropsychopharmacology 38 (2013): 23–38, https://doi.org/10.1038/npp.2012.112.

[249] Q. Zhang, J. Li, C. Wang, et al., “N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications,” Research 7 (2024): 0340, https://doi.org/10.34133/research.0340.

[250] B. Ruan, J. Dong, F. Wei, et al., “DNMT Aberration-Incurred GPX4 Suppression Prompts Osteoblast Ferroptosis and Osteoporosis,” Bone Research 12 (2024): 68, https://doi.org/10.1038/s41413-024-00365-1.

[251] X. Wang, J. Feng, Y. Xue, et al., “Structural Basis of N(6)-Adenosine Methylation by the METTL3-METTL14 Complex,” Nature 534 (2016): 575–578, https://doi.org/10.1038/nature18298.

[252] E. Sendinc and Y. Shi, “RNA m6A Methylation Across the Transcriptome,” Molecular Cell 83 (2023): 428–441, https://doi.org/10.1016/j.molcel.2023.01.006.

[253] K. D. Meyer and S. R. Jaffrey, “The Dynamic Epitranscriptome: N6-Methyladenosine and Gene Expression Control,” Nature Reviews. Molecular Cell Biology 15 (2014): 313–326, https://doi.org/10.1038/nrm3785.

[254] Y. Wu, L. Xie, M. Wang, et al., “Mettl3-Mediated m(6)A RNA Methylation Regulates the Fate of Bone Marrow Mesenchymal Stem Cells and Osteoporosis,” Nature Communications 9 (2018): 4772, https://doi.org/10.1038/s41467-018-06898-4.

[255] T. Li, J. Zhao, J. Yuan, et al., “Harnessing Engineered Exosomes as METTL3 Carriers: Enhancing Osteogenesis and Suppressing Lipogenesis in Bone Marrow Mesenchymal Stem Cells for Postmenopausal Osteoporosis Treatment,” Materials Today Bio 32 (2025): 101648, https://doi.org/10.1016/j.mtbio.2025.101648.

[256] B. Zhou, X. Feng, C. Han, et al., “YTHDF3 Regulates IL32 mRNA Stability to Promote Osteogenic Differentiation of Bone Mesenchymal Stem Cells in Ankylosing Spondylitis,” Journal of Translational Medicine 23 (2025): 604, https://doi.org/10.1186/s12967-025-06607-y.

[257] Z. W. Feng, B. Peng, S. H. Wang, et al., “METTL3-Mediated m(6)A Modification of SOX4 Regulates Osteoblast Proliferation and Differentiation via YTHDF3 Recognition,” Cellular Signalling 115 (2024): 111038, https://doi.org/10.1016/j.cellsig.2024.111038.

[258] Z. Jiang, C. Zhang, R. Liu, et al., “M(6)A Demethyltransferase FTO Attenuates Meniscus Degeneration and Osteoarthritis via Orchestrating Autophagy and Energetic Metabolism,” Advanced Science 12 (2025): e2412379, https://doi.org/10.1002/advs.202412379.

[259] W. Yao, X. Hu, and X. Wang, “Crossing Epigenetic Frontiers: The Intersection of Novel Histone Modifications and Diseases,” Signal Transduction and Targeted Therapy 9 (2024): 232, https://doi.org/10.1038/s41392-024-01918-w.

[260] W. Feng and T. Chen, “Epigenetic Modification Mediated by PHF20/METTL14/HOXA13 Signaling Axis Modulates Osteogenic Differentiation of Mesenchymal Stem Cells,” Functional & Integrative Genomics 25 (2025): 7, https://doi.org/10.1007/s10142-024-01516-7.

[261] Y. Liu, Z. Tong, C. Wang, et al., “TiO2 Nanotubes Regulate Histone Acetylation Through F-Actin to Induce the Osteogenic Differentiation of BMSCs,” Artificial Cells, Nanomedicine, and Biotechnology 49 (2021): 398–406, https://doi.org/10.1080/21691401.2021.1910282.

[262] J. Wu, M. Hu, H. Jiang, et al., “Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis,” Advanced Science (Weinheim) 10 (2023): e2301300, https://doi.org/10.1002/advs.202301300.

[263] Y. Li, W. Sun, J. Li, et al., “HuR-Mediated Nucleocytoplasmic Translocation of HOTAIR Relieves Its Inhibition of Osteogenic Differentiation and Promotes Bone Formation,” Bone Research 11 (2023): 53, https://doi.org/10.1038/s41413-023-00289-2.

[264] S. Ghafouri-Fard, H. Shoorei, M. Mohaqiq, J. Majidpoor, M. A. Moosavi, and M. Taheri, “Exploring the Role of Non-Coding RNAs in Autophagy,” Autophagy 18 (2022): 949–970, https://doi.org/10.1080/15548627.2021.1883881.

[265] C. Song, Y. Guo, F. Chen, and W. Liu, “IRF-1-Inhibited lncRNA XIST Regulated the Osteogenic Differentiation via miR-450b/FBXW7 Axis,” Apoptosis 28 (2023): 669–680, https://doi.org/10.1007/s10495-023-01820-w.

[266] X. Zhang, B. Sai, F. Wang, et al., “Hypoxic BMSC-Derived Exosomal miRNAs Promote Metastasis of Lung Cancer Cells via STAT3-Induced EMT,” Molecular Cancer 18 (2019): 40, https://doi.org/10.1186/s12943-019-0959-5.

[267] L. Q. Cao, X. W. Yang, Y. B. Chen, D. W. Zhang, X. F. Jiang, and P. Xue, “Exosomal miR-21 Regulates the TETs/PTENp1/PTEN Pathway to Promote Hepatocellular Carcinoma Growth,” Molecular Cancer 18 (2019): 148, https://doi.org/10.1186/s12943-019-1075-2.

[268] F. Olivieri, F. Prattichizzo, A. Giuliani, et al., “miR-21 and miR-146a: The microRNAs of Inflammaging and Age-Related Diseases,” Ageing Research Reviews 70 (2021): 101374, https://doi.org/10.1016/j.arr.2021.101374.

[269] S. Zhang, J. Guo, Y. He, et al., “Roles of lncRNA in the Crosstalk Between Osteogenesis and Angiogenesis in the Bone Microenvironment,” Journal of Zhejiang University. Science. B 26 (2025): 107–123, https://doi.org/10.1631/jzus.B2300607.

[270] S. Zheng, Y. B. Wang, Y. L. Yang, et al., “LncRNA MALAT1 Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells in Osteoporosis Rats Through MAPK Signaling Pathway,” European Review for Medical and Pharmacological Sciences 23 (2019): 4609–4617, https://doi.org/10.26355/eurrev_201906_18038.

[271] C. Zhang, W. Ye, M. Zhao, D. Xia, and Z. Fan, “tRNA-Derived Small RNA Changes in Bone Marrow Stem Cells Under Hypoxia and Osteogenic Conduction,” Journal of Oral Rehabilitation 50 (2023): 1487–1497, https://doi.org/10.1111/joor.13566.

[272] G. Chen, S. Wang, C. Long, et al., “PiRNA-63049 Inhibits Bone Formation Through Wnt/β-Catenin Signaling Pathway,” International Journal of Biological Sciences 17 (2021): 4409–4425, https://doi.org/10.7150/ijbs.64533.

[273] L. Li, B. Wang, X. Zhou, et al., “METTL3-Mediated Long Non-Coding RNA MIR99AHG Methylation Targets miR-4660 to Promote Bone Marrow Mesenchymal Stem Cell Osteogenic Differentiation,” Cell Cycle 22 (2023): 476–493, https://doi.org/10.1080/15384101.2022.2125751.

[274] J. Zhang, S. Li, L. Li, et al., “Exosome and Exosomal microRNA: Trafficking, Sorting, and Function,” Genomics, Proteomics & Bioinformatics 13 (2015): 17–24, https://doi.org/10.1016/j.gpb.2015.02.001.

[275] P. Duan, Y. L. Yu, Y. N. Cheng, et al., “Exosomal miR-1a-3p Derived From Glucocorticoid-Stimulated M1 Macrophages Promotes the Adipogenic Differentiation of BMSCs in Glucocorticoid-Associated Osteonecrosis of the Femoral Head by Targeting Cebpz,” Journal of Nanobiotechnology 22 (2024): 648, https://doi.org/10.1186/s12951-024-02923-5.

[276] C. A. Herberts, M. S. Kwa, and H. P. Hermsen, “Risk Factors in the Development of Stem Cell Therapy,” Journal of Translational Medicine 9 (2011): 29, https://doi.org/10.1186/1479-5876-9-29.

[277] Z. Xie, W. Yu, G. Ye, et al., “Single-Cell RNA Sequencing Analysis of Human Bone-Marrow-Derived Mesenchymal Stem Cells and Functional Subpopulation Identification,” Experimental & Molecular Medicine 54 (2022): 483–492, https://doi.org/10.1038/s12276-022-00749-5.

[278] J. C. Fitzgerald, G. Shaw, J. M. Murphy, and F. Barry, “Media Matters: Culture Medium-Dependent Hypervariable Phenotype of Mesenchymal Stromal Cells,” Stem Cell Research & Therapy 14 (2023): 363, https://doi.org/10.1186/s13287-023-03589-w.

[279] S. H. Neo, Z. Her, R. Othman, et al., “Expansion of Human Bone Marrow-Derived Mesenchymal Stromal Cells With Enhanced Immunomodulatory Properties,” Stem Cell Research & Therapy 14 (2023): 259, https://doi.org/10.1186/s13287-023-03481-7.

[280] I. D. Orge, V. L. Gadd, J. L. Barouh, et al., “Phenotype Instability of Hepatocyte-Like Cells Produced by Direct Reprogramming of Mesenchymal Stromal Cells,” Stem Cell Research & Therapy 11 (2020): 154, https://doi.org/10.1186/s13287-020-01665-z.

[281] A. Mohammadi, A. Maleki-Jamshid, D. Sanooghi, et al., “Transplantation of Human Chorion-Derived Cholinergic Progenitor Cells: A Novel Treatment for Neurological Disorders,” Molecular Neurobiology 56 (2019): 307–318, https://doi.org/10.1007/s12035-018-0968-1.

[282] J. Galipeau and L. Sensébé, “Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities,” Cell Stem Cell 22 (2018): 824–833, https://doi.org/10.1016/j.stem.2018.05.004.

[283] D. J. Prockop, M. Brenner, W. E. Fibbe, et al., “Defining the Risks of Mesenchymal Stromal Cell Therapy,” Cytotherapy 12 (2010): 576–578, https://doi.org/10.3109/14653249.2010.507330.

[284] D. Hladik, I. Höfig, U. Oestreicher, et al., “Long-Term Culture of Mesenchymal Stem Cells Impairs ATM-Dependent Recognition of DNA Breaks and Increases Genetic Instability,” Stem Cell Research & Therapy 10 (2019): 218, https://doi.org/10.1186/s13287-019-1334-6.

[285] J. Zha, L. K. Kunselman, H. M. Xie, et al., “Inducible Sbds Deletion Impairs Bone Marrow Niche Capacity to Engraft Donor Bone Marrow After Transplantation,” Blood Advances 6 (2022): 108–120, https://doi.org/10.1182/bloodadvances.2021004640.

[286] M. Brennan, A. Renaud, J. Amiaud, et al., “Pre-Clinical Studies of Bone Regeneration With Human Bone Marrow Stromal Cells and Biphasic Calcium Phosphate,” Stem Cell Research & Therapy 5 (2014): 114, https://doi.org/10.1186/scrt504.

[287] R. S. Schneider, A. C. Vela, E. K. Williams, K. E. Martin, W. A. Lam, and A. J. García, “High-Throughput On-Chip Human Mesenchymal Stromal Cell Potency Prediction,” Advanced Healthcare Materials 11 (2022): e2101995, https://doi.org/10.1002/adhm.202101995.

[288] R. Zhang, J. Ma, J. Han, W. Zhang, and J. Ma, “Mesenchymal Stem Cell Related Therapies for Cartilage Lesions and Osteoarthritis,” American Journal of Translational Research 11 (2019): 6275–6289.

[289] S. H. M. Pang, J. D'Rozario, S. Mendonca, et al., “Mesenchymal Stromal Cell Apoptosis Is Required for Their Therapeutic Function,” Nature Communications 12 (2021): 6495, https://doi.org/10.1038/s41467-021-26834-3.

[290] K. Shen, A. Duan, J. Cheng, et al., “Exosomes Derived From Hypoxia Preconditioned Mesenchymal Stem Cells Laden in a Silk Hydrogel Promote Cartilage Regeneration via the miR-205-5p/PTEN/AKT Pathway,” Acta Biomaterialia 143 (2022): 173–188, https://doi.org/10.1016/j.actbio.2022.02.026.

[291] C. Wu, Y. Zhou, W. Fan, et al., “Hypoxia-Mimicking Mesoporous Bioactive Glass Scaffolds With Controllable Cobalt Ion Release for Bone Tissue Engineering,” Biomaterials 33 (2012): 2076–2085, https://doi.org/10.1016/j.biomaterials.2011.11.042.

RIGHTS & PERMISSIONS

2026 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.