Bone defect repair remains a core research focus and tough challenge in regenerative medicine, and the osteogenic differentiation of mesenchymal stem cells (MSCs) is a crucial prerequisite for successful bone regeneration. As transmembrane cell adhesion molecules, integrins mediate interaction between MSCs and the extracellular matrix (ECM) via bidirectional signal transduction and play a central regulatory position during osteogenic differentiation. This review systematically summarizes the structural features, biological functions and subtype expression patterns of integrins. We further elaborate the underlying mechanisms by which integrins modulate MSC osteogenic differentiation through three core signaling cascades, including FAK/PI3K-Akt pathway, Wnt/β-catenin pathway and mechanochemical signal transduction. Meanwhile, this paper clarifies the upstream regulatory roles of integrins in ECM microenvironment perception, biomaterial interface response and epigenetic modification, as well as downstream effector processes involving RUNX2/OSX transcriptional cascade activation, cytoskeleton rearrangement and expression of matrix mineralization-related genes. Current controversies regarding the functional specificity and redundancy of different integrin subtypes are also discussed, and prospective applications of integrins in the development of intelligent biomaterials and precise regulation of bone tissue engineering are highlighted. In conclusion, this review comprehensively expounds the regulatory mechanisms of integrins, aiming to provide novel theoretical references and promising therapeutic strategies for bone defect regeneration and repair.

Jie Tan, Jun Li. Roles and Regulatory Mechanisms of Integrins in Osteogenic Differentiation of Mesenchymal Stem Cells. International Journal of Frontiers in Medicine (2026), Vol. 8, Issue 2: 56-63. https://doi.org/10.25236/IJFM.2026.080207.

[1] Jepsen S, Schwarz F, Cordaro L, et al. Regeneration of alveolar ridge defects. Consensus report of group 4 of the 15th European Workshop on Periodontology on Bone Regeneration [J]. Journal of clinical periodontology, 2019, 46 Suppl 21: 277-286.

[2] Miron R J. Optimized bone grafting [J]. Periodontology 2000, 2024, 94(1): 143-160.

[3] Tay J R H, Ng E, Lu X J, et al. Healing complications and their detrimental effects on bone gain in vertical-guided bone regeneration: A systematic review and meta-analysis [J]. Clinical implant dentistry and related research, 2022, 24(1): 43-71.

[4] Wang F, Zhou Y, Zhou J, et al. Comparison of Intraoral Bone Regeneration with Iliac and Alveolar BMSCs [J]. Journal of dental research, 2018, 97(11): 1229-1235.

[5] Lotfi M S, Rassouli F B. Natural Polyphenols and Mesenchymal Stem Cells: A New Insight in Bone Regenerative Medicine [J]. Stem cells international, 2025, 2025: 8019494.

[6] Zhang Y, Feng X, Zheng B, et al. Regulation and mechanistic insights into tensile strain in mesenchymal stem cell osteogenic differentiation [J]. Bone, 2024, 187: 117197.

[7] Gaus S, Li H, Li S, et al. Shared Genetic and Epigenetic Mechanisms between the Osteogenic Differentiation of Dental Pulp Stem Cells and Bone Marrow Stem Cells [J]. BioMed research international, 2021, 2021: 6697810.

[8] Li M, Gong W, Chen J, et al. PPP3R1 Promotes MSCs Senescence by Inducing Plasma Membrane Depolarization and Increasing Ca(2+) Influx [J]. International journal of molecular sciences, 2023, 24(5).

[9] Liu Y, Wang Z, Ju M, et al. Modification of COL1A1 in Autologous Adipose Tissue-Derived Progenitor Cells Rescues the Bone Phenotype in a Mouse Model of Osteogenesis Imperfecta [J]. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2021, 36(8): 1521-1534.

[10] Fu Y, Xin Z, Ling Z, et al. A CREB1-miR-181a-5p loop regulates the pathophysiologic features of bone marrow stromal cells in fibrous dysplasia of bone [J]. Molecular medicine (Cambridge, Mass), 2021, 27(1): 81.

[11] Mao L, Wang L, Xu J, et al. The role of integrin family in bone metabolism and tumor bone metastasis [J]. Cell death discovery, 2023, 9(1): 119.

[12] Tollabi M, Poursalehi Z, Mehrafshar P, et al. Insight into the role of integrins and integrins-targeting biomaterials in bone regeneration [J]. Connective tissue research, 2024, 65(5): 343-363.

[13] Xie W, Ma L, Wang P, et al. Dynamic Regulation of Cell Mechanotransduction through Sequentially Controlled Mobile Surfaces [J]. Nano letters, 2024, 24(26): 7953-7961.

[14] Barczyk M, Carracedo S, Gullberg D. Integrins [J]. Cell and tissue research, 2010, 339(1): 269-280.

[15] Mohd Arizam D N, Nordin F, Ahmad A, et al. Integrin signaling pathways in mesenchymal stem cells [J]. Stem cell research & therapy, 2025, 16(1): 472.

[16] Wang L, Zheng F, Song R, et al. Integrins in the Regulation of Mesenchymal Stem Cell Differentiation by Mechanical Signals [J]. Stem cell reviews and reports, 2022, 18(1): 126-141.

[17] Ying L, Wang C, Shi K, et al. Interpreting the Mechanisms by which Integrins Promote the Differentiation of Mesenchymal Stem Cells and Integrin Application Prospects [J]. Current stem cell research & therapy, 2021, 16(7): 848-857.

[18] Lee H M, Seo S R, Kim J, et al. Expression dynamics of integrin α2, α3, and αV upon osteogenic differentiation of human mesenchymal stem cells [J]. Stem cell research & therapy, 2020, 11(1): 210.

[19] Beiki B, Zeynali B, Taghiabadi E, et al. Osteogenic differentiation of Wharton's jelly-derived mesenchymal stem cells cultured on WJ-scaffold through conventional signalling mechanism [J]. Artificial cells, nanomedicine, and biotechnology, 2018, 46(sup3): S1032-s1042.

[20] Sun M, Chi G, Xu J, et al. Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin α5 [J]. Stem cell research & therapy, 2018, 9(1): 52.

[21] Zheng H, Tian Y, Gao Q, et al. Hierarchical Micro-Nano Topography Promotes Cell Adhesion and Osteogenic Differentiation via Integrin α2-PI3K-AKT Signaling Axis [J]. Frontiers in bioengineering and biotechnology, 2020, 8: 463.

[22] Yu K R, Yang S R, Jung J W, et al. CD49f enhances multipotency and maintains stemness through the direct regulation of OCT4 and SOX2 [J]. Stem cells (Dayton, Ohio), 2012, 30(5): 876-887.

[23] Li G W. Study on the regulation of rBMSCs morphology and function by Rho GTPases/Wnt/β-catenin signaling pathway mediated by micro/nano-topography on titanium surface [in Chinese]. Doctoral dissertation, Fourth Military Medical University, 2017.

[24] Saidak Z, Le Henaff C, Azzi S, et al. Wnt/β-catenin signaling mediates osteoblast differentiation triggered by peptide-induced α5β1 integrin priming in mesenchymal skeletal cells [J]. The Journal of biological chemistry, 2015, 290(11): 6903-6912.

[25] Hu P, Zhu X, Zhao C, et al. Fak silencing impairs osteogenic differentiation of bone mesenchymal stem cells induced by uniaxial mechanical stretch [J]. Journal of dental sciences, 2019, 14(3): 225-233.

[26] Peng Y, Qu R, Yang Y, et al. Regulation of the integrin αVβ3- actin filaments axis in early osteogenic differentiation of human mesenchymal stem cells under cyclic tensile stress [J]. Cell communication and signaling : CCS, 2023, 21(1): 308.

[27] Di Benedetto A, Brunetti G, Posa F, et al. Osteogenic differentiation of mesenchymal stem cells from dental bud: Role of integrins and cadherins [J]. Stem cell research, 2015, 15(3): 618-628.

[28] Salasznyk R M, Williams W A, Boskey A, et al. Adhesion to Vitronectin and Collagen I Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells [J]. Journal of biomedicine & biotechnology, 2004, 2004(1): 24-34.

[29] Hamidouche Z, Fromigué O, Ringe J, et al. Crosstalks between integrin alpha 5 and IGF2/IGFBP2 signalling trigger human bone marrow-derived mesenchymal stromal osteogenic differentiation [J]. BMC cell biology, 2010, 11: 44.

[30] Cheng Z A, Alba-Perez A, Gonzalez-Garcia C, et al. Nanoscale Coatings for Ultralow Dose BMP-2-Driven Regeneration of Critical-Sized Bone Defects [J]. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2019, 6(2): 1800361.

[31] Xie H, Cao T, Franco-Obregón A, et al. Graphene-Induced Osteogenic Differentiation Is Mediated by the Integrin/FAK Axis [J]. International journal of molecular sciences, 2019, 20(3).

[32] Liu H, Wu Q, Liu S, et al. The role of integrin αvβ3 in biphasic calcium phosphate ceramics mediated M2 Macrophage polarization and the resultant osteoinduction [J]. Biomaterials, 2024, 304: 122406.

[33] Zheng X, Chen L, Tan J, et al. Effect of micro/nano-sheet array structures on the osteo-immunomodulation of macrophages [J]. Regenerative biomaterials, 2022, 9: rbac075.

[34] Adithya S P, Balagangadharan K, Selvamurugan N. Epigenetic modifications of histones during osteoblast differentiation [J]. Biochimica et biophysica acta Gene regulatory mechanisms, 2022, 1865(1): 194780.

[35] Ghorbaninejad M, Khademi-Shirvan M, Hosseini S, et al. Epidrugs: novel epigenetic regulators that open a new window for targeting osteoblast differentiation [J]. Stem cell research & therapy, 2020, 11(1): 456.

[36] He S, Yang S, Zhang Y, et al. LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis [J]. Cell death & disease, 2019, 10(12): 947.

[37] Ai K, Wu Y, Liang G, et al. DNA methyltransferase Dnmt3ba-mediated epigenetic modulation of Integrin signaling is essential for hematopoietic stem and progenitor cell development [J]. Communications biology, 2025, 8(1): 1612.

[38] Chen Y, Chen Q, Zhong M, et al. miR-637 Inhibits Osteogenic Differentiation of Human Intervertebral Disc Cartilage Endplate Stem Cells by Targeting WNT5A [J]. Journal of investigative surgery : the official journal of the Academy of Surgical Research, 2022, 35(6): 1313-1321.

[39] Chen C, Jiang Z, Yang G. Laminins in osteogenic differentiation and pluripotency maintenance [J]. Differentiation; research in biological diversity, 2020, 114: 13-19.

[40] Komori T. Whole Aspect of Runx2 Functions in Skeletal Development [J]. International journal of molecular sciences, 2022, 23(10).

[41] Komori T. Regulation of Skeletal Development and Maintenance by Runx2 and Sp7 [J]. International journal of molecular sciences, 2024, 25(18).

[42] Azarkina K, Gromova E, Malashicheva A. "A Friend Among Strangers" or the Ambiguous Roles of Runx2 [J]. Biomolecules, 2024, 14(11).

[43] Shi J, Yao H, Chong H, et al. Tissue-engineered collagen matrix loaded with rat adipose-derived stem cells/human amniotic mesenchymal stem cells for rotator cuff tendon-bone repair [J]. International journal of biological macromolecules, 2024, 282(Pt 4): 137144.

[44] Hu H, Li Z, Lu M, et al. Osteoactivin inhibits dexamethasone-induced osteoporosis through up-regulating integrin β1 and activate ERK pathway [J]. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2018, 105: 66-72.

[45] Komori T. Bone development by Hedgehog and Wnt signaling, Runx2, and Sp7 [J]. Journal of bone and mineral metabolism, 2025, 43(1): 33-38.

[46] Arroyo R, López S, Romo E, et al. Carboxy-Terminal Cementum Protein 1-Derived Peptide 4 (cemp1-p4) Promotes Mineralization through wnt/β-catenin Signaling in Human Oral Mucosa Stem Cells [J]. International journal of molecular sciences, 2020, 21(4).

[47] Wu Z, Dai W, Wang P, et al. Periostin promotes migration, proliferation, and differentiation of human periodontal ligament mesenchymal stem cells [J]. Connective tissue research, 2018, 59(2): 108-119.

[48] Costa D G, Ferraz E P, Abuna R P F, et al. The effect of collagen coating on titanium with nanotopography on in vitro osteogenesis [J]. Journal of biomedical materials research Part A, 2017, 105(10): 2783-2788.

[49] Wu Y, Tang Y, Zhang X, et al. MMP-1 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via the JNK and ERK pathway [J]. The international journal of biochemistry & cell biology, 2020, 129: 105880.

[50] Ma S, Liu G, Jin L, et al. IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla [J]. Scientific reports, 2016, 6: 36922.

[51] Yang L, Chen H, Yang C, et al. Research progress on the regulatory mechanism of integrin-mediated mechanical stress in cells involved in bone metabolism [J]. Journal of cellular and molecular medicine, 2024, 28(7): e18183.