Advances in mechanotransduction signalling pathways in distraction osteogenesis_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

YANG Jinghong ^1,2,3 , JIANG Lujun ^1,2,3 , WANG Zi ^1,2,3 ,  LI Zhong ^1,2,3 ,  LIU Yanshi ^1,2,3

1. Orthopedics and Sports Medicine Center, Affiliated Hospital, Southwest Medical University, Luzhou Sichuan, 646000, P. R. China;
2. Sichuan Provincial Laboratory of Orthopaedic Engineering, Southwest Medical University, Luzhou Sichuan, 646000, P. R. China;
3. Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Southwest Medical University, Luzhou Sichuan, 646000, P. R. China;

Corresponding author：

LI Zhong, Email: lzlizhong199403@163.com; LIU Yanshi, Email: liuyanshi_1990@163.com

Keywords：

Mechanotransduction signaling pathway; distraction osteogenesis; mechanical stress; mechanosensitive ion channel

DOI：

10.7507/1002-1892.202504004

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the role and research progress of mechanotransduction signaling pathway in distraction osteogenesis, so as to provide theoretical basis and reference for clinical treatment. Methods The role and research progress of mechanical mechanotransduction signaling pathways in distraction osteogenesis were summarized by extensive review of relevant literature at home and abroad. Results The mechanotransduction signaling pathway plays a central role of “sensation-transformation-execution” in distraction osteogenesis, and activates a series of molecular mechanisms to promote the regeneration and remodeling of bone tissue by integrating external mechanical signals. Mechanical stimuli are converted into mechanotransduction signals through the perception of integrins, Piezo1 ion channels and bone cell networks. Activate downstream molecules are transduce through signal pathways such as Wnt/β-catenin, transforming growth factor β/bone morphogenetic protein-Smad, mitogen-activated protein kinase, protein kinase Hippo-Yes-associated protein/transcriptional coactivator with PDZ-binding motif, and phosphatidylinositol 3-kinase/ protein kinase B, so as to achieve the effects of promoting osteoblast proliferation, accelerating endochondral ossification, regulating bone resorption and the like, thereby promoting the regeneration of new bone in the distraction area. The study of mechanotransduction signaling pathways in distraction osteogenesis is expected to optimize the mechanical parameters of distraction osteogenesis and provide targeted intervention strategies for accelerating new bone regeneration and mineralization in the distraction zone. However, the specific mechanism of mechanotransduction signaling pathway in distraction osteogenesis remains to be further elucidated, and artificial intelligence and multi-omics analysis may be the future development direction of mechanotransduction signaling pathway. Conclusion In distraction osteogenesis, mechanotransduction signal transduction is the core mechanism of new bone regeneration in the distraction zone, which regulates cell behavior and tissue regeneration by converting mechanical stimulation into biochemical signals.

1.	臧建成, 秦泗河. 从Wolff定律和Ilizarov张力-应力法则到骨科自然重建理念. 中国骨伤, 2013, 26(4): 287-290.
2.	曲龙. Ilizarov胫骨横向骨搬移技术的起源和发展. 中医正骨, 2019, 31(10): 4-6.
3.	Zhu YL, Guo BF, Zang JC, et al. Ilizarov technology in China: a historic review of thirty-one years. Int Orthop, 2022, 46(3): 661-668.
4.	Guan S, Du H, Wu Y, et al. The Ilizarov technique: A dynamic solution for orthopaedic challenges. Orthop Surg, 2024, 16(9): 2111-2114.
5.	王天宝, 李晓飞, 张海宁, 等. 机械敏感性离子通道的研究进展. 齐鲁医学杂志, 2016, 31(3): 373-375.
6.	张珂诚, 李聪, 陈知行. 力信号转导的基本元件: 机械力敏感离子通道的研究进展. 生命科学, 2021, 33(2): 205-222.
7.	陈国辉, 李亚星, 张晖, 等. Piezo机械敏感性离子通道在骨关节系统中的作用. 中国修复重建外科杂志, 2024, 38(2): 240-248.
8.	曹希萌, 沈荧怡, 胥春. 缺氧预处理间充质干细胞来源的外泌体在骨再生中作用的研究进展. 口腔医学, 2023, 43(9): 844-848.
9.	Liu Y, Liu J, Cai F, et al. Hypoxia during the consolidation phase of distraction osteogenesis promotes bone regeneration. Front Physiol, 2022, 13: 804469. doi: 10.3389/fphys.2022.804469.
10.	Liu K, Wang S, Yalikun A, et al. The accordion technique enhances bone regeneration via angiogenesis factor in a rat distraction osteogenesis model. Front Physiol, 2023, 14: 1259567.Liu K, Wang S, Yalikun A, et al. The accordion technique enhances bone regeneration via angiogenesis factor in a rat distraction osteogenesis model. Front Physiol, 2023, 14: 1259567. doi: 10.3389/fphys.2023.1259567.
11.	Hu P, Zhu X, Zhao C, et al. Fak silencing impairs osteogenic differentiation of bone mesenchymal stem cells induced by uniaxial mechanical stretch. J Dent Sci, 2019, 14(3): 225-233.
12.	王林, 王熙, 季楠, 等. 机械激活性离子通道压电蛋白Piezo1通过Notch信号通路介导牙周膜干细胞成骨分化作用机制研究. 华西口腔医学杂志, 2020, 38(6): 628-636.
13.	Ru Y, Gu H, Sun L, et al. Mechanical stretch-induced ATP release from osteocytes promotes osteogenesis of bone marrow mesenchymal stem cells. Discov Med, 2024, 36(182): 494-508.
14.	Wang H, Li T, Wang X, et al. The role of sphingosine-1-phosphate signaling pathway in cementocyte mechanotransduction. Biochem Biophys Res Commun, 2020, 523(3): 595-601.
15.	Reilly GC, Haut TR, Yellowley CE, et al. Fluid flow induced PGE2 release by bone cells is reduced by glycocalyx degradation whereas calcium signals are not. Biorheology, 2003, 40(6): 591-603.
16.	Li K, Liu L, Zhang J, et al. TP508 promotes bone regeneration on distraction osteogenesis via the activation of Wnt/β-catenin signaling pathway. Curr Pharm Biotechnol, 2025, 26(3): 402-410.
17.	Li K, Liu L, Liu H, et al. LATS1/YAP1 axis controls bone regeneration on distraction osteogenesis by activating Wnt/β-catenin. Tissue Eng Part A, 2024, 30(3-4): 154-167.
18.	Wang X, Luo E, Bi R, et al. Wnt/β-catenin signaling is required for distraction osteogenesis in rats. Connect Tissue Res, 2018, 59(1): 45-54.
19.	Wu M, Chen G, Li YP. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res, 2016, 4: 16009. doi: 10.1038/boneres.2016.9.
20.	Wu M, Wu S, Chen W, et al. The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res, 2024, 34(2): 101-123.
21.	Xu J, Liu J, Gan Y, et al. High-dose TGF-β₁ impairs mesenchymal stem cell-mediated bone regeneration via BMP2 inhibition. J Bone Miner Res, 2020, 35(1): 167-180.
22.	Khanal A, Yoshioka I, Tominaga K, et al. The BMP signaling and its Smads in mandibular distraction osteogenesis. Oral Dis, 2008, 14(4): 347-355.
23.	Zhang P, Dai Q, Ouyang N, et al. Mechanical strain promotes osteogenesis of BMSCs from ovariectomized rats via the ERK1/2 but not p38 or JNK-MAPK signaling pathways. Curr Mol Med, 2015, 15(8): 780-789.
24.	Zhang P, Wu Y, Dai Q, et al. p38-MAPK signaling pathway is not involved in osteogenic differentiation during early response of mesenchymal stem cells to continuous mechanical strain. Mol Cell Biochem, 2013, 378(1-2): 19-28.
25.	Chen J, Hua J, Song W. Screen key genes associated with distraction-induced osteogenesis of stem cells using bioinformatics methods. Int J Mol Sci, 2021, 22(12): 6505. doi: 10.3390/ijms22126505.
26.	Wang F, Li S, Kong L, et al. Tensile stress-activated and exosome-transferred YAP/TAZ-notch circuit specifies type H endothelial cell for segmental bone regeneration. Adv Sci (Weinh), 2024, 11(12): e2309133. doi: 10.1002/advs.202309133.
27.	Li S, Wu H, Wang F, et al. Enhanced bone regeneration through regulation of mechanoresponsive FAK-ERK1/2 signaling by ZINC40099027 during distraction osteogenesis. Int J Med Sci, 2024, 21(1): 137-150.
28.	Watabe H, Furuhama T, Tani-Ishii N, et al. Mechanotransduction activates α₅β₁ integrin and PI3K/Akt signaling pathways in mandibular osteoblasts. Exp Cell Res, 2011, 317(18): 2642-2649.
29.	Jiang W, Zhu P, Huang F, et al. The RNA methyltransferase METTL3 promotes endothelial progenitor cell angiogenesis in mandibular distraction osteogenesis via the PI3K/AKT pathway. Front Cell Dev Biol, 2021, 9: 720925. doi: 10.3389/fcell.2021.720925.
30.	Wang D, Cai J, Zeng Z, et al. The interactions between mTOR and NF-κB: A novel mechanism mediating mechanical stretch-stimulated osteoblast differentiation. J Cell Physiol, 2020. doi: 10.1002/jcp.30184.
31.	Ransom RC, Carter AC, Salhotra A, et al. Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration. Nature, 2018, 563(7732): 514-521.
32.	Motie P, Mohaghegh S, Kouhestani F, et al. Effect of mechanical forces on the behavior of osteoblasts: a systematic review of in vitro studies. Dent Med Probl, 2023, 60(4): 673-686.
33.	Li Z, Zheng J, Wan D, et al. Uniaxial static strain promotes osteoblast proliferation and bone matrix formation in distraction osteogenesis in vitro. Biomed Res Int, 2020, 2020: 3906426. doi: 10.1155/2020/3906426.
34.	Xiao LW, Yang M, Dong J, et al. Stretch-inducible expression of connective tissue growth factor (CTGF) in human osteoblasts-like cells is mediated by PI3K-JNK pathway. Cell Physiol Biochem, 2011, 28(2): 297-304.
35.	Meyer U, Meyer T, Wiesmann HP, et al. Mechanical tension in distraction osteogenesis regulates chondrocytic differentiation. Int J Oral Maxillofac Surg, 2001, 30(6): 522-530.
36.	曲延征, 陈伟辉, 蔡志宇, 等. 山羊下颌骨牵张成骨过程中血管生成与新骨形成关系的实验研究. 福建医药杂志, 2007, 29(5): 109-111.
37.	Zhang L, Peng Y, Guo T, et al. Uniaxial static strain enhances osteogenic and angiogenic potential under hypoxic conditions in distraction osteogenesis. J Orthop Surg Res, 2024, 19(1): 711. doi: 10.1186/s13018-024-05212-x.
38.	Li J, Wan Z, Liu H, et al. Osteoblasts subjected to mechanical strain inhibit osteoclastic differentiation and bone resorption in a co-culture system. Ann Biomed Eng, 2013, 41(10): 2056-2066.
39.	Uchinuma M, Taketani Y, Kanaya R, et al. Role of Piezo1 in modulating the RANKL/OPG ratio in mouse osteoblast cells exposed to Porphyromonas gingivalis lipopolysaccharide and mechanical stress. J Periodontal Res, 2024, 59(4): 749-757.
40.	Kitcharanant N, Chattipakorn N, Chattipakorn SC. The effect of intermittent parathyroid hormone on bone lengthening: current evidence to inform future effective interventions. Osteoporos Int, 2023, 34(10): 1657-1675.
41.	Inada N, Ohata T, Maruno H, et al. Optimal timing for intermittent administration of parathyroid hormone (1-34) for distraction osteogenesis in rabbits. J Orthop Surg Res, 2022, 17(1): 130. doi: 10.1186/s13018-022-03019-2.
42.	Yamashita J, McCauley LK. Effects of intermittent administration of parathyroid hormone and parathyroid hormone-related protein on fracture healing: A narrative review of animal and human studies. JBMR Plus, 2019, 3(12): e10250. doi: 10.1002/jbm4.10250.
43.	Altay B, Dede EÇ, Özgul Ö, et al. Effect of systemic oxytocin administration on new bone formation and distraction rate in rabbit mandible. J Oral Maxillofac Surg, 2020, 78(7): 1171-1182.
44.	Acikan I, Mehmet G, Artas G, et al. Systemic melatonin application increases bone formation in mandibular distraction osteogenesis. Braz Oral Res, 2018, 32: e85. doi: 10.1590/1807-3107bor-2018.vol32.0085.
45.	Wang F, Kong L, Wang W, et al. Adrenomedullin 2 improves bone regeneration in type 1 diabetic rats by restoring imbalanced macrophage polarization and impaired osteogenesis. Stem Cell Res Ther, 2021, 12(1): 288. doi: 10.1186/s13287-021-02368-9.
46.	Wang F, Qian H, Kong L, et al. Accelerated bone regeneration by astragaloside Ⅳ through stimulating the coupling of osteogenesis and angiogenesis. Int J Biol Sci, 2021, 17(7): 1821-1836.
47.	Lin H, Wang X, Li Z, et al. Total flavonoids of Rhizoma drynariae promote angiogenesis and osteogenesis in bone defects. Phytother Res, 2022, 36(9): 3584-3600.
48.	Li Y, Pan Q, Xu J, et al. Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals. J Orthop Translat, 2021, 27: 110-118.
49.	Hamushan M, Cai W, Zhang Y, et al. High-purity magnesium pin enhances bone consolidation in distraction osteogenesis via regulating Ptch protein activating Hedgehog-alternative Wnt signaling. Bioact Mater, 2020, 6(6): 1563-1574.
50.	Zhao G, Wang S, Wang G, et al. Enhancing bone formation using absorbable AZ31B magnesium alloy membranes during distraction osteogenesis: A new material study. Heliyon, 2023, 9(8): e18032. doi: 10.1016/j.heliyon.2023.e18032.
51.	Lou T, Chen K, Luo Q, et al. Periosteum-inspired in situ CaP generated nanocomposite hydrogels with strong bone adhesion and superior stretchability for accelerated distraction osteogenesis. Biomater Res, 2022, 26(1): 91. doi: 10.1186/s40824-022-00330-1.
52.	Liu X, Sun Y, Shen J, et al. Strontium doped mesoporous silica nanoparticles accelerate osteogenesis and angiogenesis in distraction osteogenesis by activation of Wnt pathway. Nanomedicine, 2022, 41: 102496. doi: 10.1016/j.nano.2021.102496.
53.	Liu Y, Cai F, Liu K, et al. Cyclic distraction-compression dynamization technique enhances the bone formation during distraction osteogenesis. Front Bioeng Biotechnol, 2022, 9: 810723. doi: 10.3389/fbioe.2021.810723.
54.	庄嘉宝, 胥春. 机械力刺激诱导机体组织炎症反应机制研究进展. 医用生物力学, 2017, 32(5): 476-480.
55.	Liao F, Zhang T, Jiang W, et al. Characterization of the angiogenic and proteomic features of circulating exosomes in a canine mandibular model of distraction osteogenesis. J Proteome Res, 2024, 23(11): 4924-4939.
56.	Jiang WD, Zhu PQ, Zhang T, et al. PRRX1+MSCs enhance mandibular regeneration during distraction osteogenesis. J Dent Res, 2023, 102(9): 1058-1068.

1. 臧建成, 秦泗河. 从Wolff定律和Ilizarov张力-应力法则到骨科自然重建理念. 中国骨伤, 2013, 26(4): 287-290.
2. 曲龙. Ilizarov胫骨横向骨搬移技术的起源和发展. 中医正骨, 2019, 31(10): 4-6.
3. Zhu YL, Guo BF, Zang JC, et al. Ilizarov technology in China: a historic review of thirty-one years. Int Orthop, 2022, 46(3): 661-668.
4. Guan S, Du H, Wu Y, et al. The Ilizarov technique: A dynamic solution for orthopaedic challenges. Orthop Surg, 2024, 16(9): 2111-2114.
5. 王天宝, 李晓飞, 张海宁, 等. 机械敏感性离子通道的研究进展. 齐鲁医学杂志, 2016, 31(3): 373-375.
6. 张珂诚, 李聪, 陈知行. 力信号转导的基本元件: 机械力敏感离子通道的研究进展. 生命科学, 2021, 33(2): 205-222.
7. 陈国辉, 李亚星, 张晖, 等. Piezo机械敏感性离子通道在骨关节系统中的作用. 中国修复重建外科杂志, 2024, 38(2): 240-248.
8. 曹希萌, 沈荧怡, 胥春. 缺氧预处理间充质干细胞来源的外泌体在骨再生中作用的研究进展. 口腔医学, 2023, 43(9): 844-848.
9. Liu Y, Liu J, Cai F, et al. Hypoxia during the consolidation phase of distraction osteogenesis promotes bone regeneration. Front Physiol, 2022, 13: 804469. doi: 10.3389/fphys.2022.804469.
10. Liu K, Wang S, Yalikun A, et al. The accordion technique enhances bone regeneration via angiogenesis factor in a rat distraction osteogenesis model. Front Physiol, 2023, 14: 1259567.Liu K, Wang S, Yalikun A, et al. The accordion technique enhances bone regeneration via angiogenesis factor in a rat distraction osteogenesis model. Front Physiol, 2023, 14: 1259567. doi: 10.3389/fphys.2023.1259567.
11. Hu P, Zhu X, Zhao C, et al. Fak silencing impairs osteogenic differentiation of bone mesenchymal stem cells induced by uniaxial mechanical stretch. J Dent Sci, 2019, 14(3): 225-233.
12. 王林, 王熙, 季楠, 等. 机械激活性离子通道压电蛋白Piezo1通过Notch信号通路介导牙周膜干细胞成骨分化作用机制研究. 华西口腔医学杂志, 2020, 38(6): 628-636.
13. Ru Y, Gu H, Sun L, et al. Mechanical stretch-induced ATP release from osteocytes promotes osteogenesis of bone marrow mesenchymal stem cells. Discov Med, 2024, 36(182): 494-508.
14. Wang H, Li T, Wang X, et al. The role of sphingosine-1-phosphate signaling pathway in cementocyte mechanotransduction. Biochem Biophys Res Commun, 2020, 523(3): 595-601.
15. Reilly GC, Haut TR, Yellowley CE, et al. Fluid flow induced PGE2 release by bone cells is reduced by glycocalyx degradation whereas calcium signals are not. Biorheology, 2003, 40(6): 591-603.
16. Li K, Liu L, Zhang J, et al. TP508 promotes bone regeneration on distraction osteogenesis via the activation of Wnt/β-catenin signaling pathway. Curr Pharm Biotechnol, 2025, 26(3): 402-410.
17. Li K, Liu L, Liu H, et al. LATS1/YAP1 axis controls bone regeneration on distraction osteogenesis by activating Wnt/β-catenin. Tissue Eng Part A, 2024, 30(3-4): 154-167.
18. Wang X, Luo E, Bi R, et al. Wnt/β-catenin signaling is required for distraction osteogenesis in rats. Connect Tissue Res, 2018, 59(1): 45-54.
19. Wu M, Chen G, Li YP. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res, 2016, 4: 16009. doi: 10.1038/boneres.2016.9.
20. Wu M, Wu S, Chen W, et al. The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res, 2024, 34(2): 101-123.
21. Xu J, Liu J, Gan Y, et al. High-dose TGF-β₁ impairs mesenchymal stem cell-mediated bone regeneration via BMP2 inhibition. J Bone Miner Res, 2020, 35(1): 167-180.
22. Khanal A, Yoshioka I, Tominaga K, et al. The BMP signaling and its Smads in mandibular distraction osteogenesis. Oral Dis, 2008, 14(4): 347-355.
23. Zhang P, Dai Q, Ouyang N, et al. Mechanical strain promotes osteogenesis of BMSCs from ovariectomized rats via the ERK1/2 but not p38 or JNK-MAPK signaling pathways. Curr Mol Med, 2015, 15(8): 780-789.
24. Zhang P, Wu Y, Dai Q, et al. p38-MAPK signaling pathway is not involved in osteogenic differentiation during early response of mesenchymal stem cells to continuous mechanical strain. Mol Cell Biochem, 2013, 378(1-2): 19-28.
25. Chen J, Hua J, Song W. Screen key genes associated with distraction-induced osteogenesis of stem cells using bioinformatics methods. Int J Mol Sci, 2021, 22(12): 6505. doi: 10.3390/ijms22126505.
26. Wang F, Li S, Kong L, et al. Tensile stress-activated and exosome-transferred YAP/TAZ-notch circuit specifies type H endothelial cell for segmental bone regeneration. Adv Sci (Weinh), 2024, 11(12): e2309133. doi: 10.1002/advs.202309133.
27. Li S, Wu H, Wang F, et al. Enhanced bone regeneration through regulation of mechanoresponsive FAK-ERK1/2 signaling by ZINC40099027 during distraction osteogenesis. Int J Med Sci, 2024, 21(1): 137-150.
28. Watabe H, Furuhama T, Tani-Ishii N, et al. Mechanotransduction activates α₅β₁ integrin and PI3K/Akt signaling pathways in mandibular osteoblasts. Exp Cell Res, 2011, 317(18): 2642-2649.
29. Jiang W, Zhu P, Huang F, et al. The RNA methyltransferase METTL3 promotes endothelial progenitor cell angiogenesis in mandibular distraction osteogenesis via the PI3K/AKT pathway. Front Cell Dev Biol, 2021, 9: 720925. doi: 10.3389/fcell.2021.720925.
30. Wang D, Cai J, Zeng Z, et al. The interactions between mTOR and NF-κB: A novel mechanism mediating mechanical stretch-stimulated osteoblast differentiation. J Cell Physiol, 2020. doi: 10.1002/jcp.30184.
31. Ransom RC, Carter AC, Salhotra A, et al. Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration. Nature, 2018, 563(7732): 514-521.
32. Motie P, Mohaghegh S, Kouhestani F, et al. Effect of mechanical forces on the behavior of osteoblasts: a systematic review of in vitro studies. Dent Med Probl, 2023, 60(4): 673-686.
33. Li Z, Zheng J, Wan D, et al. Uniaxial static strain promotes osteoblast proliferation and bone matrix formation in distraction osteogenesis in vitro. Biomed Res Int, 2020, 2020: 3906426. doi: 10.1155/2020/3906426.
34. Xiao LW, Yang M, Dong J, et al. Stretch-inducible expression of connective tissue growth factor (CTGF) in human osteoblasts-like cells is mediated by PI3K-JNK pathway. Cell Physiol Biochem, 2011, 28(2): 297-304.
35. Meyer U, Meyer T, Wiesmann HP, et al. Mechanical tension in distraction osteogenesis regulates chondrocytic differentiation. Int J Oral Maxillofac Surg, 2001, 30(6): 522-530.
36. 曲延征, 陈伟辉, 蔡志宇, 等. 山羊下颌骨牵张成骨过程中血管生成与新骨形成关系的实验研究. 福建医药杂志, 2007, 29(5): 109-111.
37. Zhang L, Peng Y, Guo T, et al. Uniaxial static strain enhances osteogenic and angiogenic potential under hypoxic conditions in distraction osteogenesis. J Orthop Surg Res, 2024, 19(1): 711. doi: 10.1186/s13018-024-05212-x.
38. Li J, Wan Z, Liu H, et al. Osteoblasts subjected to mechanical strain inhibit osteoclastic differentiation and bone resorption in a co-culture system. Ann Biomed Eng, 2013, 41(10): 2056-2066.
39. Uchinuma M, Taketani Y, Kanaya R, et al. Role of Piezo1 in modulating the RANKL/OPG ratio in mouse osteoblast cells exposed to Porphyromonas gingivalis lipopolysaccharide and mechanical stress. J Periodontal Res, 2024, 59(4): 749-757.
40. Kitcharanant N, Chattipakorn N, Chattipakorn SC. The effect of intermittent parathyroid hormone on bone lengthening: current evidence to inform future effective interventions. Osteoporos Int, 2023, 34(10): 1657-1675.
41. Inada N, Ohata T, Maruno H, et al. Optimal timing for intermittent administration of parathyroid hormone (1-34) for distraction osteogenesis in rabbits. J Orthop Surg Res, 2022, 17(1): 130. doi: 10.1186/s13018-022-03019-2.
42. Yamashita J, McCauley LK. Effects of intermittent administration of parathyroid hormone and parathyroid hormone-related protein on fracture healing: A narrative review of animal and human studies. JBMR Plus, 2019, 3(12): e10250. doi: 10.1002/jbm4.10250.
43. Altay B, Dede EÇ, Özgul Ö, et al. Effect of systemic oxytocin administration on new bone formation and distraction rate in rabbit mandible. J Oral Maxillofac Surg, 2020, 78(7): 1171-1182.
44. Acikan I, Mehmet G, Artas G, et al. Systemic melatonin application increases bone formation in mandibular distraction osteogenesis. Braz Oral Res, 2018, 32: e85. doi: 10.1590/1807-3107bor-2018.vol32.0085.
45. Wang F, Kong L, Wang W, et al. Adrenomedullin 2 improves bone regeneration in type 1 diabetic rats by restoring imbalanced macrophage polarization and impaired osteogenesis. Stem Cell Res Ther, 2021, 12(1): 288. doi: 10.1186/s13287-021-02368-9.
46. Wang F, Qian H, Kong L, et al. Accelerated bone regeneration by astragaloside Ⅳ through stimulating the coupling of osteogenesis and angiogenesis. Int J Biol Sci, 2021, 17(7): 1821-1836.
47. Lin H, Wang X, Li Z, et al. Total flavonoids of Rhizoma drynariae promote angiogenesis and osteogenesis in bone defects. Phytother Res, 2022, 36(9): 3584-3600.
48. Li Y, Pan Q, Xu J, et al. Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals. J Orthop Translat, 2021, 27: 110-118.
49. Hamushan M, Cai W, Zhang Y, et al. High-purity magnesium pin enhances bone consolidation in distraction osteogenesis via regulating Ptch protein activating Hedgehog-alternative Wnt signaling. Bioact Mater, 2020, 6(6): 1563-1574.
50. Zhao G, Wang S, Wang G, et al. Enhancing bone formation using absorbable AZ31B magnesium alloy membranes during distraction osteogenesis: A new material study. Heliyon, 2023, 9(8): e18032. doi: 10.1016/j.heliyon.2023.e18032.
51. Lou T, Chen K, Luo Q, et al. Periosteum-inspired in situ CaP generated nanocomposite hydrogels with strong bone adhesion and superior stretchability for accelerated distraction osteogenesis. Biomater Res, 2022, 26(1): 91. doi: 10.1186/s40824-022-00330-1.
52. Liu X, Sun Y, Shen J, et al. Strontium doped mesoporous silica nanoparticles accelerate osteogenesis and angiogenesis in distraction osteogenesis by activation of Wnt pathway. Nanomedicine, 2022, 41: 102496. doi: 10.1016/j.nano.2021.102496.
53. Liu Y, Cai F, Liu K, et al. Cyclic distraction-compression dynamization technique enhances the bone formation during distraction osteogenesis. Front Bioeng Biotechnol, 2022, 9: 810723. doi: 10.3389/fbioe.2021.810723.
54. 庄嘉宝, 胥春. 机械力刺激诱导机体组织炎症反应机制研究进展. 医用生物力学, 2017, 32(5): 476-480.
55. Liao F, Zhang T, Jiang W, et al. Characterization of the angiogenic and proteomic features of circulating exosomes in a canine mandibular model of distraction osteogenesis. J Proteome Res, 2024, 23(11): 4924-4939.
56. Jiang WD, Zhu PQ, Zhang T, et al. PRRX1+MSCs enhance mandibular regeneration during distraction osteogenesis. J Dent Res, 2023, 102(9): 1058-1068.

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