Research progress on mechanism of traumatic brain injury promoting fracture healing_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LI Huairen ¹ , HAN Fengping ¹ , MENG Jing ² , CHANG Wenli ² ,  FENG Li ²

1. School of Clinical Medicine, Jining Medical University, Jining Shandong, 272000, P. R. China;
2. Department of Emergency Trauma Surgery, the First People’s Hospital of Jining, Jining Shandong, 272000, P. R. China;

Corresponding author：

FENG Li, Email: fengli19811010@163.com

Keywords：

Traumatic brain injury; fracture healing; cytokines; hormones; neurokines; inflammation

DOI：

10.7507/1002-1892.202310045

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the research progress on the mechanism related to traumatic brain injury (TBI) to promote fracture healing, and to provide theoretical basis for clinical treatment of fracture non-union. Methods The research literature on TBI to promote fracture healing at home and abroad was reviewed, the role of TBI in fracture healing was summarized from three aspects of nerves, body fluids, and immunity, to explore new ideas for the treatment of fracture non-union. Results Numerous studies have shown that fracture healing is faster in patients with fracture combined with TBI than in patients with simple fracture. It is found that the expression of various cytokines and hormones in the body fluids of patients with fracture and TBI is significantly higher than that of patients with simple fracture, and the neurofactors released by the nervous system reaches the fracture site through the damaged blood-brain barrier, and the chemotaxis and aggregation of inflammatory cells and inflammatory factors at the fracture end of patients with combined TBI also differs significantly from those of patients with simple fracture. A complex network of humoral, neural, and immunomodulatory networks together promote regeneration of blood vessels at the fracture site, osteoblasts differentiation, and inhibition of osteoclasts activity. Conclusion TBI promotes fracture healing through a complex network of neural, humoral, and immunomodulatory, and can treat fracture non-union by intervening in the perifracture microenvironment.

Citation： LI Huairen, HAN Fengping, MENG Jing, CHANG Wenli, FENG Li. Research progress on mechanism of traumatic brain injury promoting fracture healing. Chinese Journal of Reparative and Reconstructive Surgery, 2024, 38(1): 125-132. doi: 10.7507/1002-1892.202310045 Copy

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1. Zhang M, Xu F, Cao J, et al. Research advances of nanomaterials for the acceleration of fracture healing. Bioact Mater, 2023, 31: 368-394.
2. Calandriello B. Callus formation in severe brain injuries. Bull Hosp Joint Dis, 1964, 25: 170-175.
3. Haffner-Luntzer M, Weber B, Morioka K, et al. Altered early immune response after fracture and traumatic brain injury. Front Immunol, 2023, 14: 1074207.
4. Yang C, Gao C, Liu N, et al. The effect of traumatic brain injury on bone healing from a novel exosome centered perspective in a mice model. J Orthop Translat, 2021, 30: 70-81.
5. Davis EL, Davis AR, Gugala Z, et al. Is heterotopic ossification getting nervous?: The role of the peripheral nervous system in heterotopic ossification. Bone, 2018, 109: 22-27.
6. Yang YQ, Tan YY, Wong R, et al. The role of vascular endothelial growth factor in ossification. Int J Oral Sci, 2012, 4(2): 64-68.
7. Bluteau G, Julien M, Magne D, et al. VEGF and VEGF receptors are differentially expressed in chondrocytes. Bone, 2007, 40(3): 568-576.
8. Liu Y, Berendsen AD, Jia S, et al. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest, 2012, 122(9): 3101-3113.
9. Berendsen AD, Olsen BR. How vascular endothelial growth factor-A (VEGF) regulates differentiation of mesenchymal stem cells. J Histochem Cytochem, 2014, 62(2): 103-108.
10. Yuan X, Luo Q, Shen L, et al. Hypoxic preconditioning enhances the differentiation of bone marrow stromal cells into mature oligodendrocytes via the mTOR/HIF-1α/VEGF pathway in traumatic brain injury. Brain Behav, 2020, 10(7): e01675.
11. Tian H, Yang X, Zhao J, et al. Hypoxia-preconditioned bone marrow mesenchymal stem cells improved cerebral collateral circulation and stroke outcome in mice. Arterioscler Thromb Vasc Biol, 2023, 43(7): 1281-1294.
12. Maes C, Goossens S, Bartunkova S, et al. Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones. EMBO J, 2010, 29(2): 424-441.
13. 李继庆, 郭征, 韩金安, 等. 脑损伤合并骨折与单纯骨折患者血管内皮生长因子的表达及其临床意义. 中国组织工程研究与临床康复, 2009, 13(28): 5453-5456.
14. Mayr-Wohlfart U, Waltenberger J, Hausser H, et al. Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone, 2002, 30(3): 472-477.
15. Zhang R, Liang Y, Wei S. The expressions of NGF and VEGF in the fracture tissues are closely associated with accelerated clavicle fracture healing in patients with traumatic brain injury. Ther Clin Risk Manag, 2018, 14: 2315-2322.
16. Wang WD, Cheng BZ, Kang WB, et al. Investigation for TGF-β₁ expression in type 2 diabetes and protective effects of TGF-β₁ on osteoblasts under high glucose environment. Eur Rev Med Pharmacol Sci, 2018, 22(19): 6500-6506.
17. Xia C, Ge Q, Fang L, et al. TGF-β/Smad2 signalling regulates enchondral bone formation of Gli1+ periosteal cells during fracture healing. Cell Prolif, 2020, 53(11): e12904.
18. 马维, 牛彦平, 张华. 合并脑损伤大鼠骨折愈合过程中转化生长因子β1血清含量及在骨折位点的表达. 中国临床康复, 2006, 10(42): 88-91, 封面.
19. Ducy P, Karsenty G. The family of bone morphogenetic proteins. Kidney Int, 2000, 57(6): 2207-2214.
20. Kawai S, Faucheu C, Gallea S, et al. Mouse smad8 phosphorylation downstream of BMP receptors ALK-2, ALK-3, and ALK-6 induces its association with Smad4 and transcriptional activity. Biochem Biophys Res Commun, 2000, 271(3): 682-687.
21. Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev, 2005, 19(23): 2783-2810.
22. Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction. J Biochem, 2010, 147(1): 35-51.
23. Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev, 2005, 16(3): 251-263.
24. Nishimura R, Hata K, Matsubara T, et al. Regulation of bone and cartilage development by network between BMP signalling and transcription factors. J Biochem, 2012, 151(3): 247-254.
25. Nolan K, Thompson TB. The DAN family: modulators of TGF-β signaling and beyond. Protein Sci, 2014, 23(8): 999-1012.
26. Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res, 2002, 17(3): 513-520.
27. 郭启, 张柳. 脑外伤对骨折愈合中骨形成蛋白2表达的影响. 中国修复重建外科杂志, 2007, 21(10): 1040-1044.
28. Xie Y, Zinkle A, Chen L, et al. Fibroblast growth factor signalling in osteoarthritis and cartilage repair. Nat Rev Rheumatol, 2020, 16(10): 547-564.
29. Li X, Wang C, Xiao J, et al. Fibroblast growth factors, old kids on the new block. Semin Cell Dev Biol, 2016, 53: 155-167.
30. Taketomi T, Onimura T, Yoshiga D, et al. Sprouty2 is involved in the control of osteoblast proliferation and differentiation through the FGF and BMP signaling pathways. Cell Biol Int, 2018, 42(9): 1106-1114.
31. Schmidt A, Ladage D, Schinköthe T, et al. Basic fibroblast growth factor controls migration in human mesenchymal stem cells. Stem Cells, 2006, 24(7): 1750-1758.
32. Choi SC, Kim SJ, Choi JH, et al. Fibroblast growth factor-2 and -4 promote the proliferation of bone marrow mesenchymal stem cells by the activation of the PI3K-Akt and ERK1/2 signaling pathways. Stem Cells Dev, 2008, 17(4): 725-736.
33. Matsushita T, Chan YY, Kawanami A, et al. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol Cell Biol, 2009, 29(21): 5843-5857.
34. Mollahosseini M, Ahmadirad H, Goujani R, et al. The association between traumatic brain injury and accelerated fracture healing: A study on the effects of growth factors and cytokines. J Mol Neurosci, 2021, 71(1): 162-168.
35. Steppan CM, Crawford DT, Chidsey-Frink KL, et al. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept, 2000, 92(1-3): 73-78.
36. Turner RT, Kalra SP, Wong CP, et al. Peripheral leptin regulates bone formation. J Bone Miner Res, 2013, 28(1): 22-34.
37. Iwaniec UT, Boghossian S, Lapke PD, et al. Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice. Peptides, 2007, 28(5): 1012-1019.
38. Yan H, Zhang HW, Fu P, et al. Leptin’s effect on accelerated fracture healing after traumatic brain injury. Neurol Res, 2013, 35(5): 537-544.
39. Graef F, Seemann R, Garbe A, et al. Impaired fracture healing with high non-union rates remains irreversible after traumatic brain injury in leptin-deficient mice. J Musculoskelet Neuronal Interact, 2017, 17(2): 78-85.
40. Seemann R, Graef F, Garbe A, et al. Leptin-deficiency eradicates the positive effect of traumatic brain injury on bone healing: histological analyses in a combined trauma mouse model. J Musculoskelet Neuronal Interact, 2018, 18(1): 32-41.
41. Garbe A, Graef F, Appelt J, et al. Leptin mediated pathways stabilize posttraumatic insulin and osteocalcin patterns after long bone fracture and concomitant traumatic brain injury and thus influence fracture healing in a combined murine trauma model. Int J Mol Sci, 2020, 21(23): 9144.
42. Murphy MG, Bach MA, Plotkin D, et al. Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study Group. J Bone Miner Res, 1999, 14(7): 1182-1188.
43. 孙良智, 张柳, 王守君, 等. 大鼠股骨骨折合并脑损伤骨折愈合过程中胰岛素样生长因子Ⅰ在血清和骨痂中的表达. 中国临床康复, 2006, 10(40): 60-62, 插图40-42.
44. Bagherifard A, Hosseinzadeh A, Koosha F, et al. Melatonin and bone-related diseases: an updated mechanistic overview of current evidence and future prospects. Osteoporos Int, 2023, 34(10): 1677-1701.
45. Lu X, Yu S, Chen G, et al. Insight into the roles of melatonin in bone tissue and bone-related diseases (Review). Int J Mol Med, 2021, 47(5): 82.
46. Shino H, Hasuike A, Arai Y, et al. Melatonin enhances vertical bone augmentation in rat calvaria secluded spaces. Med Oral Patol Oral Cir Bucal, 2016, 21(1): e122-e126.
47. Sethi S, Radio NM, Kotlarczyk MP, et al. Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways. J Pineal Res, 2010, 49(3): 222-238.
48. Dong P, Gu X, Zhu G, et al. Melatonin induces osteoblastic differentiation of mesenchymal stem cells and promotes fracture healing in a rat model of femoral fracture via neuropeptide Y/neuropeptide Y Receptor Y1 signaling. Pharmacology, 2018, 102(5-6): 272-280.
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Chinese Journal of Reparative and Reconstructive Surgery

Research progress on mechanism of traumatic brain injury promoting fracture healing

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