Melatonin promotes osteogenesis of bone marrow mesenchymal stem cells by improving the inflammatory state in ovariectomized rats_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

GUAN Huanshuai , CAO Ruomu , ZHAO Yiwei , ZHANG Jiewen , LI Heng , DUAN Xudong , LI Yiyang , KONG Ning , TIAN Run , WANG Kunzheng ,  YANG Pei

Department of Bone and Joint Surgery, Xi’an Jiaotong University Second Affiliated Hospital, Xi’an Shaanxi, 710004, P. R. China;

Corresponding author：

YANG Pei, Email: yangpei@xjtu.edu.cn

Keywords：

Melatonin; osteoporosis; inflammatory factor; lipopolysaccharide; osteogenic capacity

DOI：

10.7507/1002-1892.202304001

Video：

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Objective To investigate the effects of melatonin (MT) on bone mass and serum inflammatory factors in rats received ovariectomy (OVX) and to investigate the effects of MT on the levels of inflammatory factors in culture medium and osteogenic ability of bone marrow mesenchymal stem cells (BMSCs) stimulated by lipopolysaccharide. Methods Fifteen 12-week-old Sprague Dawley (SD) rats were randomly divided into 3 groups. The rats in Sham group only received bilateral lateral abdominal incision and suture, the rats in OVX group received bilateral OVX, and the rats in OVX+MT group received 100 mg/(kg·d) MT oral intervention after bilateral OVX. After 8 weeks, the levels of serum inflammatory factors [interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α)] were detected using ELISA assay. Besides, the distal femurs were detected by Micro-CT to observe changes in bone mass and microstructure, and quantitatively measured bone volume fraction, trabecular thickness, and trabecular number. The BMSCs were extracted from the femurs of three 3-week-old SD rats using whole bone marrow culture method and passaged. The 3rd-5th passage BMSCs were cultured with different concentrations of MT (0, 1, 10, 100, 1 000 µmol/L), and the cell viability was then detected using cell counting kit 8 (CCK-8) to select the optimal concentration of MT for subsequent experiments. Cells were devided into osteogenic induction group (group A) and osteogenic induction+1/5/10 μg/mL lipopolysaccharide group (group B-D). The levels of inflammatory factors (IL-1β, IL-6 and TNF-α) in cell culture medium were detected using ELISA assay after corresponding intervention. According to the results of CCK-8 method and ELISA detection, the cells were intervened with the most significant concentration of lipopolysaccharide for stimulating inflammation and the optimal concentration of MT with osteogenic induction, defining as group E, and the cell culture medium was collected to detect the levels of inflammatory factors by ELISA assay. After that, alkaline phosphatase (ALP) staining and alizarin red staining were performed respectively in groups A, D, and E, and the expression levels of osteogenic related genes [collagen type Ⅰ alpha 1 chain (Col1a1) and RUNX family transcription factor 2 (Runx2)] were also detected by real time fluorescence quantitative PCR (RT-qPCR). Results ELISA and Micro-CT assays showed that compared with Sham group, the bone mass of the rats in the OVX group significantly decreased, and the expression levels of serum inflammatory factors (IL-1β, IL-6, and TNF-α) in OVX group significantly increased (P<0.05). Significantly, the above indicators in OVX+MT group were all improved (P<0.05). Rat BMSCs were successfully extracted, and CCK-8 assay showed that 100 µmol/L was the maximum concentration of MT that did not cause a decrease in cell viability, and it was used in subsequent experiments. ELISA assays showed that compared with group A, the expression levels of inflammatory factors (IL-1β, IL-6, and TNF-α) in the cell culture medium of groups B-D were significantly increased after lipopolysaccharide stimulation (P<0.05), and in a concentration-dependent manner. Moreover, the expression levels of inflammatory factors in group D were significantly higher than those in groups B and C (P<0.05). After MT intervention, the expression levels of inflammatory factors in group E were significantly lower than those in group D (P<0.05). ALP staining, alizarin red staining, and RT-qPCR assays showed that compared with group A, the percentage of positive area of ALP and alizarin red and the relative mRNA expressions of Col1a1 and Runx2 in group D significantly decreased, while the above indicators in group E significantly improved after MT intervention (P<0.05). Conclusion MT may affect the bone mass of postmenopausal osteoporosis by reducing inflammation in rats; MT can reduce the inflammation of BMSCs stimulated by lipopolysaccharide and weaken its inhibition of osteogenic differentiation of BMSCs.

Citation： GUAN Huanshuai, CAO Ruomu, ZHAO Yiwei, ZHANG Jiewen, LI Heng, DUAN Xudong, LI Yiyang, KONG Ning, TIAN Run, WANG Kunzheng, YANG Pei. Melatonin promotes osteogenesis of bone marrow mesenchymal stem cells by improving the inflammatory state in ovariectomized rats. Chinese Journal of Reparative and Reconstructive Surgery, 2023, 37(8): 1011-1020. doi: 10.7507/1002-1892.202304001 Copy

1.	Peng J, Chen J, Liu Y, et al. Association between periodontitis and osteoporosis in United States adults from the National Health and Nutrition Examination Survey: a cross-sectional analysis. BMC Oral Health, 2023, 23(1): 254.
2.	Gao Y, Chen N, Fu Z, et al. Progress of Wnt signaling pathway in osteoporosis. Biomolecules, 2023, 13(3): 483.
3.	段克友, 刘翔宇, 熊风, 等. 绝经后骨质疏松症患者发生骨质疏松性椎体压缩骨折危险因素分析. 山东医药, 2021, 61(24): 34-38.
4.	Zheng M, Wan Y, Liu G, et al. Differences in the prevalence and risk factors of osteoporosis in chinese urban and rural regions: a cross-sectional study. BMC Musculoskelet Disord, 2023, 24(1): 46.
5.	彭永德. 骨质疏松症的药物治疗进展. 中国临床保健杂志, 2022, 25(1): 17-21.
6.	Iantomasi T, Romagnoli C, Palmini G, et al. Oxidative stress and inflammation in osteoporosis: Molecular mechanisms involved and the relationship with microRNAs. Int J Mol Sci, 2023, 24(4): 3772.
7.	Damani JJ, De Souza MJ, Strock NCA, et al. Associations between inflammatory mediators and bone outcomes in postmenopausal women: A cross-sectional analysis of baseline data from the prune study. J Inflamm Res, 2023, 16: 639-663.
8.	Matsuda K, Shiba N, Hiraoka K. New insights into the role of synovial fibroblasts leading to joint destruction in rheumatoid arthritis. Int J Mol Sci, 2023, 24(6): 5173.
9.	Mo Q, Zhang W, Zhu A, et al. Regulation of osteogenic differentiation by the pro-inflammatory cytokines IL-1β and TNF-α: current conclusions and controversies. Hum Cell, 2022, 35(4): 957-971.
10.	Cline-Smith A, Axelbaum A, Shashkova E, et al. Ovariectomy activates chronic low-grade inflammation mediated by memory T cells, which promotes osteoporosis in mice. J Bone Miner Res, 2020, 35(6): 1174-1187.
11.	Pietschmann P, Mechtcheriakova D, Meshcheryakova A, et al. Immunology of osteoporosis: A mini-review. Gerontology, 2016, 62(2): 128-137.
12.	Khandelwal S, Lane NE. Osteoporosis: Review of etiology, mechanisms, and approach to management in the aging population. Endocrinol Metab Clin North Am, 2023, 52(2): 259-275.
13.	Wu D, Cline-Smith A, Shashkova E, et al. T-cell mediated inflammation in postmenopausal osteoporosis. Front Immunol, 2021, 12: 687551.
14.	Huang R, Chen Y, Tu M, et al. Monocyte to high-density lipoprotein and apolipoprotein A1 ratios are associated with bone homeostasis imbalance caused by chronic inflammation in postmenopausal women with type 2 diabetes mellitus. Front Pharmacol, 2022, 13: 1062999.
15.	Wang Z, Zhang X, Cheng X, et al. Inflammation produced by senescent osteocytes mediates age-related bone loss. Front Immunol, 2023, 14: 1114006.
16.	Zhang J, Jiang J, Qin Y, et al. Systemic immune-inflammation index is associated with decreased bone mass density and osteoporosis in postmenopausal women but not in premenopausal women. Endocr Connect, 2023, 12(2): e220461.
17.	Faria VS, Messias LHD, Pejon TMM, et al. Influence of acute melatonin administration on human physical performance: A systematic review. Sports Health, 2023, 19417381231155142. doi: 10.1177/19417381231155142.
18.	Yang K, Qiu X, Cao L, et al. The role of melatonin in the development of postmenopausal osteoporosis. Front Pharmacol, 2022, 13: 975181.
19.	Ren M, Liu H, Jiang W, et al. Melatonin repairs osteoporotic bone defects in iron-overloaded rats through PI3K/AKT/GSK-3 β/P70S6k signaling pathway. Oxid Med Cell Longev, 2023, 2023: 7718155.
20.	Da W, Tao L, Wen K, et al. Protective role of melatonin against postmenopausal bone loss via enhancement of citrate secretion from osteoblasts. Front Pharmacol, 2020, 11: 667.
21.	Zhang J, Jia G, Xue P, et al. Melatonin restores osteoporosis-impaired osteogenic potential of bone marrow mesenchymal stem cells and alleviates bone loss through the HGF/ PTEN/ Wnt/β-catenin axis. Ther Adv Chronic Dis, 2021, 12: 2040622321995685. doi: 10.1177/2040622321995685.
22.	Zhou Y, Wang C, Si J, et al. Melatonin up-regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2 -inactivated NF-κB pathway. Br J Pharmacol, 2020, 177(9): 2106-2122.
23.	Liu Y, Zhang Y, Mei N, et al. Three acidic polysaccharides derived from sour jujube seeds protect intestinal epithelial barrier function in LPS induced Caco-2 cell inflammation model. Int J Biol Macromol, 2023, 240: 124435.
24.	Zhou R, Chen F, Liu H, et al. Berberine ameliorates the LPS-induced imbalance of osteogenic and adipogenic differentiation in rat bone marrow-derived mesenchymal stem cells. Mol Med Rep, 2021, 23(5): 350.
25.	Huang X, Chen W, Gu C, et al. Melatonin suppresses bone marrow adiposity in ovariectomized rats by rescuing the imbalance between osteogenesis and adipogenesis through SIRT1 activation. J Orthop Translat, 2022, 38: 84-97.
26.	Ostrowska Z, Kos-Kudla B, Swietochowska E, et al. Assessment of the relationship between dynamic pattern of nighttime levels of melatonin and chosen biochemical markers of bone metabolism in a rat model of postmenopausal osteoporosis. Neuro Endocrinol Lett, 2001, 22(2): 129-136.
27.	Cao L, Yang K, Yuan W, et al. Melatonin mediates osteoblast proliferation through the STIM1/ORAI1 pathway. Front Pharmacol, 2022, 13: 851663.
28.	Egermann M, Gerhardt C, Barth A, et al. Pinealectomy affects bone mineral density and structure—an experimental study in sheep. BMC Musculoskelet Disord, 2011, 12: 271.
29.	Choi JH, Jang AR, Park MJ, et al. Melatonin inhibits osteoclastogenesis and bone loss in ovariectomized mice by regulating PRMT1-mediated signaling. Endocrinology, 2021, 162(6): bqab057.
30.	Mundy GR. Osteoporosis and inflammation. Nutr Rev, 2007, 65(12 Pt 2): S147-S151.
31.	Romas E, Gillespie MT. Inflammation-induced bone loss: can it be prevented? Rheum Dis Clin North Am, 2006, 32(4): 759-773.
32.	Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov, 2012, 11(3): 234-250.
33.	高燕, 胡鑫鑫. 绝经后骨质疏松症妇女血清炎性因子及骨代谢指标水平变化分析. 健康研究, 2022, 42(1): 41-43, 48.
34.	李建军, 石馨, 聂敏媛, 等. 绝经期骨质疏松女性牙周状况、炎性水平及骨代谢生化指标的研究. 中国妇幼健康研究, 2021, 32(11): 1613-1617.
35.	姬笑颜, 李含笑, 杨艳妮, 等. 瑞香素对去卵巢大鼠炎性因子和骨代谢的影响. 中国中医骨伤科杂志, 2021, 29(7): 17-20, 24.
36.	李佳洋, 沈沐瑶, 孙菁, 等. 培本固疏方对去卵巢大鼠炎性因子、骨生物力学及JNK/p38信号通路的影响. 中医药信息, 2021, 38(6): 35-40.
37.	Mohamad NV, Ima-Nirwana S, Chin KY. Are oxidative stress and inflammation mediators of bone loss due to estrogen deficiency? A review of current evidence. Endocr Metab Immune Disord Drug Targets, 2020, 20(9): 1478-1487.
38.	Li X, Zhang H, Qiao S, et al. Melatonin administration alleviates 2, 2, 4, 4-tetra-brominated diphenyl ether (PBDE-47)-induced necroptosis and secretion of inflammatory factors via miR-140-5p/TLR4/NF-κB axis in fish kidney cells. Fish Shellfish Immunol, 2022, 128: 228-237.
39.	Gu F, Zhang K, Li J, et al. Changes of migration, immunore-gulation and osteogenic differentiation of mesenchymal stem cells in different stages of inflammation. Int J Med Sci, 2022, 19(1): 25-33.
40.	Munir H, Ward LSC, Sheriff L, et al. Adipogenic differentiation of mesenchymal stem cells alters their immunomodulatory properties in a tissue-specific manner. Stem Cells, 2017, 35(6): 1636-1646.
41.	Zhu J, Tang H, Zhang Z, et al. Kaempferol slows intervertebral disc degeneration by modifying LPS-induced osteogenesis/adipogenesis imbalance and inflammation response in BMSCs. Int Immunopharmacol, 2017, 43: 236-242.
42.	He S, Zhang H, Lu Y, et al. Nampt promotes osteogenic differentiation and lipopolysaccharide-induced interleukin-6 secretion in osteoblastic MC3T3-E1 cells. Aging (Albany NY), 2021, 13(4): 5150-5163.
43.	Li Z, Zhao H, Chu S, et al. miR-124-3p promotes BMSC osteogenesis via suppressing the GSK-3β/β-catenin signaling pathway in diabetic osteoporosis rats. In Vitro Cell Dev Biol Anim, 2020, 56(9): 723-734.
44.	Zhang L, Su P, Xu C, et al. Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARγ expression and enhancing Runx2 expression. J Pineal Res, 2010, 49(4): 364-372.
45.	Han H, Tian T, Huang G, et al. The lncRNA H19/miR-541-3p/Wnt/β-catenin axis plays a vital role in melatonin-mediated osteogenic differentiation of bone marrow mesenchymal stem cells. Aging (Albany NY), 2021, 13(14): 18257-18273.
46.	刘合栋, 任茂贤, 李杨, 等. 褪黑素对H₂O₂诱导的成骨细胞氧化应激损伤的保护作用. 中国骨质疏松杂志, 2022, 28(8): 1093-1098.
47.	Chen H, Liu Y, Yu S, et al. Cannabidiol attenuates periodontal inflammation through inhibiting TLR4/NF-κB pathway. J Periodontal Res, 2023. doi: 10.1111/jre.13118.

1. Peng J, Chen J, Liu Y, et al. Association between periodontitis and osteoporosis in United States adults from the National Health and Nutrition Examination Survey: a cross-sectional analysis. BMC Oral Health, 2023, 23(1): 254.
2. Gao Y, Chen N, Fu Z, et al. Progress of Wnt signaling pathway in osteoporosis. Biomolecules, 2023, 13(3): 483.
3. 段克友, 刘翔宇, 熊风, 等. 绝经后骨质疏松症患者发生骨质疏松性椎体压缩骨折危险因素分析. 山东医药, 2021, 61(24): 34-38.
4. Zheng M, Wan Y, Liu G, et al. Differences in the prevalence and risk factors of osteoporosis in chinese urban and rural regions: a cross-sectional study. BMC Musculoskelet Disord, 2023, 24(1): 46.
5. 彭永德. 骨质疏松症的药物治疗进展. 中国临床保健杂志, 2022, 25(1): 17-21.
6. Iantomasi T, Romagnoli C, Palmini G, et al. Oxidative stress and inflammation in osteoporosis: Molecular mechanisms involved and the relationship with microRNAs. Int J Mol Sci, 2023, 24(4): 3772.
7. Damani JJ, De Souza MJ, Strock NCA, et al. Associations between inflammatory mediators and bone outcomes in postmenopausal women: A cross-sectional analysis of baseline data from the prune study. J Inflamm Res, 2023, 16: 639-663.
8. Matsuda K, Shiba N, Hiraoka K. New insights into the role of synovial fibroblasts leading to joint destruction in rheumatoid arthritis. Int J Mol Sci, 2023, 24(6): 5173.
9. Mo Q, Zhang W, Zhu A, et al. Regulation of osteogenic differentiation by the pro-inflammatory cytokines IL-1β and TNF-α: current conclusions and controversies. Hum Cell, 2022, 35(4): 957-971.
10. Cline-Smith A, Axelbaum A, Shashkova E, et al. Ovariectomy activates chronic low-grade inflammation mediated by memory T cells, which promotes osteoporosis in mice. J Bone Miner Res, 2020, 35(6): 1174-1187.
11. Pietschmann P, Mechtcheriakova D, Meshcheryakova A, et al. Immunology of osteoporosis: A mini-review. Gerontology, 2016, 62(2): 128-137.
12. Khandelwal S, Lane NE. Osteoporosis: Review of etiology, mechanisms, and approach to management in the aging population. Endocrinol Metab Clin North Am, 2023, 52(2): 259-275.
13. Wu D, Cline-Smith A, Shashkova E, et al. T-cell mediated inflammation in postmenopausal osteoporosis. Front Immunol, 2021, 12: 687551.
14. Huang R, Chen Y, Tu M, et al. Monocyte to high-density lipoprotein and apolipoprotein A1 ratios are associated with bone homeostasis imbalance caused by chronic inflammation in postmenopausal women with type 2 diabetes mellitus. Front Pharmacol, 2022, 13: 1062999.
15. Wang Z, Zhang X, Cheng X, et al. Inflammation produced by senescent osteocytes mediates age-related bone loss. Front Immunol, 2023, 14: 1114006.
16. Zhang J, Jiang J, Qin Y, et al. Systemic immune-inflammation index is associated with decreased bone mass density and osteoporosis in postmenopausal women but not in premenopausal women. Endocr Connect, 2023, 12(2): e220461.
17. Faria VS, Messias LHD, Pejon TMM, et al. Influence of acute melatonin administration on human physical performance: A systematic review. Sports Health, 2023, 19417381231155142. doi: 10.1177/19417381231155142.
18. Yang K, Qiu X, Cao L, et al. The role of melatonin in the development of postmenopausal osteoporosis. Front Pharmacol, 2022, 13: 975181.
19. Ren M, Liu H, Jiang W, et al. Melatonin repairs osteoporotic bone defects in iron-overloaded rats through PI3K/AKT/GSK-3 β/P70S6k signaling pathway. Oxid Med Cell Longev, 2023, 2023: 7718155.
20. Da W, Tao L, Wen K, et al. Protective role of melatonin against postmenopausal bone loss via enhancement of citrate secretion from osteoblasts. Front Pharmacol, 2020, 11: 667.
21. Zhang J, Jia G, Xue P, et al. Melatonin restores osteoporosis-impaired osteogenic potential of bone marrow mesenchymal stem cells and alleviates bone loss through the HGF/ PTEN/ Wnt/β-catenin axis. Ther Adv Chronic Dis, 2021, 12: 2040622321995685. doi: 10.1177/2040622321995685.
22. Zhou Y, Wang C, Si J, et al. Melatonin up-regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2 -inactivated NF-κB pathway. Br J Pharmacol, 2020, 177(9): 2106-2122.
23. Liu Y, Zhang Y, Mei N, et al. Three acidic polysaccharides derived from sour jujube seeds protect intestinal epithelial barrier function in LPS induced Caco-2 cell inflammation model. Int J Biol Macromol, 2023, 240: 124435.
24. Zhou R, Chen F, Liu H, et al. Berberine ameliorates the LPS-induced imbalance of osteogenic and adipogenic differentiation in rat bone marrow-derived mesenchymal stem cells. Mol Med Rep, 2021, 23(5): 350.
25. Huang X, Chen W, Gu C, et al. Melatonin suppresses bone marrow adiposity in ovariectomized rats by rescuing the imbalance between osteogenesis and adipogenesis through SIRT1 activation. J Orthop Translat, 2022, 38: 84-97.
26. Ostrowska Z, Kos-Kudla B, Swietochowska E, et al. Assessment of the relationship between dynamic pattern of nighttime levels of melatonin and chosen biochemical markers of bone metabolism in a rat model of postmenopausal osteoporosis. Neuro Endocrinol Lett, 2001, 22(2): 129-136.
27. Cao L, Yang K, Yuan W, et al. Melatonin mediates osteoblast proliferation through the STIM1/ORAI1 pathway. Front Pharmacol, 2022, 13: 851663.
28. Egermann M, Gerhardt C, Barth A, et al. Pinealectomy affects bone mineral density and structure—an experimental study in sheep. BMC Musculoskelet Disord, 2011, 12: 271.
29. Choi JH, Jang AR, Park MJ, et al. Melatonin inhibits osteoclastogenesis and bone loss in ovariectomized mice by regulating PRMT1-mediated signaling. Endocrinology, 2021, 162(6): bqab057.
30. Mundy GR. Osteoporosis and inflammation. Nutr Rev, 2007, 65(12 Pt 2): S147-S151.
31. Romas E, Gillespie MT. Inflammation-induced bone loss: can it be prevented? Rheum Dis Clin North Am, 2006, 32(4): 759-773.
32. Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov, 2012, 11(3): 234-250.
33. 高燕, 胡鑫鑫. 绝经后骨质疏松症妇女血清炎性因子及骨代谢指标水平变化分析. 健康研究, 2022, 42(1): 41-43, 48.
34. 李建军, 石馨, 聂敏媛, 等. 绝经期骨质疏松女性牙周状况、炎性水平及骨代谢生化指标的研究. 中国妇幼健康研究, 2021, 32(11): 1613-1617.
35. 姬笑颜, 李含笑, 杨艳妮, 等. 瑞香素对去卵巢大鼠炎性因子和骨代谢的影响. 中国中医骨伤科杂志, 2021, 29(7): 17-20, 24.
36. 李佳洋, 沈沐瑶, 孙菁, 等. 培本固疏方对去卵巢大鼠炎性因子、骨生物力学及JNK/p38信号通路的影响. 中医药信息, 2021, 38(6): 35-40.
37. Mohamad NV, Ima-Nirwana S, Chin KY. Are oxidative stress and inflammation mediators of bone loss due to estrogen deficiency? A review of current evidence. Endocr Metab Immune Disord Drug Targets, 2020, 20(9): 1478-1487.
38. Li X, Zhang H, Qiao S, et al. Melatonin administration alleviates 2, 2, 4, 4-tetra-brominated diphenyl ether (PBDE-47)-induced necroptosis and secretion of inflammatory factors via miR-140-5p/TLR4/NF-κB axis in fish kidney cells. Fish Shellfish Immunol, 2022, 128: 228-237.
39. Gu F, Zhang K, Li J, et al. Changes of migration, immunore-gulation and osteogenic differentiation of mesenchymal stem cells in different stages of inflammation. Int J Med Sci, 2022, 19(1): 25-33.
40. Munir H, Ward LSC, Sheriff L, et al. Adipogenic differentiation of mesenchymal stem cells alters their immunomodulatory properties in a tissue-specific manner. Stem Cells, 2017, 35(6): 1636-1646.
41. Zhu J, Tang H, Zhang Z, et al. Kaempferol slows intervertebral disc degeneration by modifying LPS-induced osteogenesis/adipogenesis imbalance and inflammation response in BMSCs. Int Immunopharmacol, 2017, 43: 236-242.
42. He S, Zhang H, Lu Y, et al. Nampt promotes osteogenic differentiation and lipopolysaccharide-induced interleukin-6 secretion in osteoblastic MC3T3-E1 cells. Aging (Albany NY), 2021, 13(4): 5150-5163.
43. Li Z, Zhao H, Chu S, et al. miR-124-3p promotes BMSC osteogenesis via suppressing the GSK-3β/β-catenin signaling pathway in diabetic osteoporosis rats. In Vitro Cell Dev Biol Anim, 2020, 56(9): 723-734.
44. Zhang L, Su P, Xu C, et al. Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARγ expression and enhancing Runx2 expression. J Pineal Res, 2010, 49(4): 364-372.
45. Han H, Tian T, Huang G, et al. The lncRNA H19/miR-541-3p/Wnt/β-catenin axis plays a vital role in melatonin-mediated osteogenic differentiation of bone marrow mesenchymal stem cells. Aging (Albany NY), 2021, 13(14): 18257-18273.
46. 刘合栋, 任茂贤, 李杨, 等. 褪黑素对H₂O₂诱导的成骨细胞氧化应激损伤的保护作用. 中国骨质疏松杂志, 2022, 28(8): 1093-1098.
47. Chen H, Liu Y, Yu S, et al. Cannabidiol attenuates periodontal inflammation through inhibiting TLR4/NF-κB pathway. J Periodontal Res, 2023. doi: 10.1111/jre.13118.

Chinese Journal of Reparative and Reconstructive Surgery

Melatonin promotes osteogenesis of bone marrow mesenchymal stem cells by improving the inflammatory state in ovariectomized rats

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