Hepatocyte growth factor and insulin-like growth factor-1 were used to repair bone-cartilage defects in bone marrow mesenchymal stem cells in a rabbit model of postmenopausal

  • Jia-Qi Guan School of Clinical Medical, Shandong Second Medical University, Weifang 261053, China; National Tissue Engineering Center of China, Shanghai 261053, China
  • Chuan-Bo Zang School of Anesthesiology, Shandong Second Medical University, Weifang 216053, China
  • Jun-Cen Li School of Clinical Medical, Shandong Second Medical University, Weifang 261053, China; National Tissue Engineering Center of China, Shanghai 261053, China
  • Fei-Fan Chen National Tissue Engineering Center of China, Shanghai 261053, China
  • Ya-Hui Wang National Tissue Engineering Center of China, Shanghai 261053, China
  • Guang-Dong Zhou School of Clinical Medical, Shandong Second Medical University, Weifang 261053, China; National Tissue Engineering Center of China, Shanghai 261053, China; Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Stem Cell Institute, Shanghai 2000336, China
  • Yu Liu School of Clinical Medical, Shandong Second Medical University, Weifang 261053, China; National Tissue Engineering Center of China, Shanghai 261053, China; Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Stem Cell Institute, Shanghai 2000336, China
  • Yi-Lin Cao School of Clinical Medical, Shandong Second Medical University, Weifang 261053, China; National Tissue Engineering Center of China, Shanghai 261053, China; Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Stem Cell Institute, Shanghai 2000336, China
DOI: https://doi.org/10.62617/mcb.v21.72
Keywords: postmenopausal osteoporosis; bone marrow mesenchymal stem cells; transcriptome sequencing; osteochondral defect; tissue engineering
Article ID: 72

Abstract

In postmenopausal osteoporosis (PMOP), an imbalance exists in the differentiation of bone marrow mesenchymal stem cells (BMSCs), with a decrease in osteogenic differentiation and an increase in adipogenic differentiation. This imbalance leads to bone marrow adiposity, bone loss, bone fragility, and a substantial rise in fracture risk. After a patient experiences an osteochondral defect due to trauma, it struggles to heal naturally, presenting a clinical challenge for treatment. Our study delved into the abnormal differentiation of BMSCs in PMOP by conducting transcriptome sequencing on BMSCs from a PMOP model (PMOP-BMSCs) and a healthy control model (Normal-BMSCs). We identified insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) genesas significantly low-expressed protein-coding genes during the osteogenic cartilage differentiation process of PMOP-BMSCs. Due to the downregulation of its expression, it leads to the deletion of the proteins it encodes IGF-1 and HGF. In order to verify the sequencing results, the feasibility of co-culture the above two growth factors with PMOP-BMSCs to repair osteochondral defects was discussed. The findings indicated that the inclusion of elements enhanced the DNA replication activity and extracellular matrix mineralization of PMOP-BMSCs. It also promoted the construction of tissue-engineered bone in vitro and the up- regulation of Runx2, BMP4, OCN, ACAN, collagen type Ⅰ, II, and Sox9 osteochondral differentiation markers. In the rabbit model of knee osteochondral injury with PMOP, the group treated with both growth factors and PMOP-BMSCs showed superior outcomes in repairing cartilage and subchondral bone defects compared to the other groups. We suggest that the addition of HGF and IGF-1 increases the expression of osteoblast and cartilage-related genes and proteins, promoting the proliferation and differentiation of osteochondrous bone in PMOP-BMSCs. These findings could offer a novel cell therapy strategy for treating postmenopausal osteoporosis, utilizing growth factors.

References

1. Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends in Endocrinology & Metabolism. 2012; 23(11): 576-581. doi: 10.1016/j.tem.2012.03.008

2. Awasthi H, Mani D, Singh D, et al. The underlying pathophysiology and therapeutic approaches for osteoporosis. Medicinal Research Reviews. 2018; 38(6): 2024-2057. doi: 10.1002/med.21504

3. Neve A, Corrado A, Cantatore FP. Osteoblast physiology in normal and pathological conditions. Cell and Tissue Research. 2010; 343(2): 289-302. doi: 10.1007/s00441-010-1086-1

4. Zhou GD, Wang XY, Miao CL, et al. Repairing porcine knee joint osteochondral defects at non-weight bearing area by autologous BMSC. Zhonghua Yi Xue Za Zhi. 2004; 84(11): 925-931.

5. Jilka RL. Biology of the basic multicellular unit and the pathophysiology of osteoporosis. Medical and Pediatric Oncology. 2003; 41(3): 182-185. doi: 10.1002/mpo.10334

6. Wu H, Yin G, Pu X, et al. Coordination of Osteoblastogenesis and Osteoclastogenesis by the Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Matrix to Promote Bone Regeneration. ACS Applied Bio Materials. 2022; 5(6): 2913-2927. doi: 10.1021/acsabm.2c00264

7. Li J, Lu L, Liu L, et al. The unique role of bone marrow adipose tissue in ovariectomy-induced bone loss in mice. Endocrine. 2023; 83(1): 77-91. doi: 10.1007/s12020-023-03504-6

8. Justesen J, Stenderup K, Kassem MS. Mesenchymal stem cells. Potential use in cell and gene therapy of bone loss caused by aging and osteoporosis. Ugeskr Laeger. 2001; 163(40): 5491-5495.

9. Bidwell JP, Alvarez MB, Hood M, et al. Functional Impairment of Bone Formation in the Pathogenesis of Osteoporosis: The Bone Marrow Regenerative Competence. Current Osteoporosis Reports. 2013; 11(2): 117-125. doi: 10.1007/s11914-013-0139-2

10. Li J, Chen X, Lu L, et al. The relationship between bone marrow adipose tissue and bone metabolism in postmenopausal osteoporosis. Cytokine & Growth Factor Reviews. 2020; 52: 88-98. doi: 10.1016/j.cytogfr.2020.02.003

11. Schmidt AH. Autologous bone graft: Is it still the gold standard? Injury. 2021; 52: S18-S22. doi: 10.1016/j.injury.2021.01.043

12. Myeroff C, Archdeacon M. Autogenous Bone Graft: Donor Sites and Techniques. Journal of Bone and Joint Surgery. 2011; 93(23): 2227-2236. doi: 10.2106/jbjs.j.01513

13. McGovern JA, Griffin M, Hutmacher DW. Animal models for bone tissue engineering and modelling disease. Disease Models & Mechanisms. 2018; 11(4). doi: 10.1242/dmm.033084

14. Chen L, Liu J, Guan M, et al. Growth Factor and Its Polymer Scaffold-Based Delivery System for Cartilage Tissue Engineering. International Journal of Nanomedicine. 2020; 15: 6097-6111. doi: 10.2147/ijn.s249829

15. Bayer EA, Gottardi R, Fedorchak MV, et al. The scope and sequence of growth factor delivery for vascularized bone tissue regeneration. Journal of Controlled Release. 2015; 219: 129-140. doi: 10.1016/j.jconrel.2015.08.004

16. Liu Y, Peng L, Li L, et al. 3D-bioprinted BMSC-laden biomimetic multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model. Biomaterials. 2021; 279: 121216. doi: 10.1016/j.biomaterials.2021.121216

17. Bei HP, Hung PM, Yeung HL, et al. Bone‐a‐Petite: Engineering Exosomes towards Bone, Osteochondral, and Cartilage Repair. Small. 2021; 17(50). doi: 10.1002/smll.202101741

18. Luo J, Chen H, Wang G, et al. CGRP‐Loaded Porous Microspheres Protect BMSCs for Alveolar Bone Regeneration in the Periodontitis Microenvironment. Advanced Healthcare Materials. 2023; 12(28). doi: 10.1002/adhm.202301366

19. Wei H, Liu K, Wang T, et al. FNDC5 overexpression promotes the survival rate of bone marrow mesenchymal stem cells after transplantation in a rat cerebral infarction model. Annals of Translational Medicine. 2022; 10(2): 90. doi: 10.21037/atm-21-6868

20. Nie WB, Zhang D, Wang LS. Growth Factor Gene-Modified Mesenchymal Stem Cells in Tissue Regeneration. Drug Design, Development and Therapy. 2020; 14: 1241-1256. doi: 10.2147/dddt.s243944

21. Fei Z, Sun C, Peng X, et al. Krüppel-like factor 4 promotes the proliferation and osteogenic differentiation of BMSCs through SOX2/IGF2 pathway. Acta Biochim Pol. 2022; 69(2): 349-355.

22. Miao X, Yuan J, Wu J, et al. Bone Morphogenetic Protein-2 Promotes Osteoclasts-mediated Osteolysis via Smad1 and p65 Signaling Pathways. Spine. 2020; 46(4): E234-E242. doi: 10.1097/brs.0000000000003770

23. Wanderman NR, Mallet C, Giambini H, et al. An Ovariectomy-Induced Rabbit Osteoporotic Model: A New Perspective. Asian Spine Journal. 2018; 12(1): 12-17. doi: 10.4184/asj.2018.12.1.12

24. Baofeng L, Zhi Y, Bei C, et al. Characterization of a rabbit osteoporosis model induced by ovariectomy and glucocorticoid. Acta Orthopaedica. 2010; 81(3): 396-401. doi: 10.3109/17453674.2010.483986

25. Zhang YW, Cao MM, Li YJ, et al. Fecal microbiota transplantation ameliorates bone loss in mice with ovariectomy-induced osteoporosis via modulating gut microbiota and metabolic function. Journal of Orthopaedic Translation. 2022; 37: 46-60. doi: 10.1016/j.jot.2022.08.003

26. Yang X, Chen Z, Chen C, et al. Bleomycin induces fibrotic transformation of bone marrow stromal cells to treat height loss of intervertebral disc through the TGFβR1/Smad2/3 pathway. Stem Cell Research & Therapy. 2021; 12(1). doi: 10.1186/s13287-020-02093-9

27. Zhong XM, Zhang L, Yao XL, et al. MicroRNA-22-3p Regulates the Expression of Kruppel-like Factor 6 to Affect the Cardiomyocyte-like Differentiation of Bone Marrow Mesenchymal Stem Cell. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2023; 45(1): 1-8.

28. Gao L, Gong FZ, Ma LY, et al. Uncarboxylated osteocalcin promotes osteogenesis and inhibits adipogenesis of mouse bone marrow‑derived mesenchymal stem cells via the PKA‑AMPK‑SIRT1 axis. Experimental and Therapeutic Medicine. 2021; 22(2). doi: 10.3892/etm.2021.10312

29. Wang Y, Xu Y, Zhou G, et al. Biological Evaluation of Acellular Cartilaginous and Dermal Matrixes as Tissue Engineering Scaffolds for Cartilage Regeneration. Frontiers in Cell and Developmental Biology. 2021; 8. doi: 10.3389/fcell.2020.624337

30. Zhang Y, Huang X, Sun K, et al. The Potential Role of Serum IGF-1 and Leptin as Biomarkers: Towards Screening for and Diagnosing Postmenopausal Osteoporosis. Journal of Inflammation Research. 2022; 15: 533-543. doi: 10.2147/jir.s344009

31. Torres L, Klingberg E, Nurkkala M, et al. Hepatocyte growth factor is a potential biomarker for osteoproliferation and osteoporosis in ankylosing spondylitis. Osteoporosis International. 2018; 30(2): 441-449. doi: 10.1007/s00198-018-4721-4

32. Xian L, Wu X, Pang L, et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nature Medicine. 2012; 18(7): 1095-1101. doi: 10.1038/nm.2793

33. Skrtic S, Ohlsson C. Cortisol Decreases Hepatocyte Growth Factor Levels in Human Osteoblast-Like Cells. Calcified Tissue International. 2000; 66(2): 108-112. doi: 10.1007/pl00005831

34. Shen Y, Jiang B, Luo B, et al. Circular RNA-FK501 binding protein 51 boosts bone marrow mesenchymal stem cell proliferation and osteogenic differentiation via modulating microRNA-205-5p/Runt-associated transcription factor 2 axis. Journal of Orthopaedic Surgery and Research. 2023; 18(1). doi: 10.1186/s13018-023-04242-1

35. Chen S, Jia L, Zhang S, et al. DEPTOR regulates osteogenic differentiation via inhibiting MEG3-mediated activation of BMP4 signaling and is involved in osteoporosis. Stem Cell Research & Therapy. 2018; 9(1). doi: 10.1186/s13287-018-0935-9

36. Chen J, Jia Z, Zhang F, et al. HGF-modified human umbilical cord mesenchymal stem cells rescue impaired ovarian reserve function in chemotherapy-induced POI rats by improving angiogenesis while decreasing apoptosis and fibrosis in the ovary. Tissue and Cell. 2023; 82: 102121. doi: 10.1016/j.tice.2023.102121

37. Sani M, Hosseinie R, Latifi M, et al. Engineered artificial articular cartilage made of decellularized extracellular matrix by mechanical and IGF-1 stimulation. Biomaterials Advances. 2022; 139: 213019. doi: 10.1016/j.bioadv.2022.213019

38. Yuan F, Chen H, Hu P, et al. MiR-26a regulates the expression of serum IGF-1 in patients with osteoporosis and its effect on proliferation and apoptosis of mouse chondrocytes. J Musculoskelet Neuronal Interact. 2021; 21(2): 298-307.

39. Hossain MA, Adithan A, Alam MJ, et al. IGF-1 Facilitates Cartilage Reconstruction by Regulating PI3K/AKT, MAPK, and NF-kB Signaling in Rabbit Osteoarthritis. Journal of Inflammation Research. 2021; 14: 3555-3568. doi: 10.2147/jir.s316756

40. Kong F, Shi X, Xiao F, et al. Transplantation of Hepatocyte Growth Factor–Modified Dental Pulp Stem Cells Prevents Bone Loss in the Early Phase of Ovariectomy-Induced Osteoporosis. Human Gene Therapy. 2018; 29(2): 271-282. doi: 10.1089/hum.2017.091

41. Ellison GM, Torella D, Dellegrottaglie S, et al. Endogenous Cardiac Stem Cell Activation by Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Intracoronary Injection Fosters Survival and Regeneration of the Infarcted Pig Heart. Journal of the American College of Cardiology. 2011; 58(9): 977-986. doi: 10.1016/j.jacc.2011.05.013

42. Koudstaal S, Bastings MMC, Feyen DAM, et al. Sustained Delivery of Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Stimulates Endogenous Cardiac Repair in the Chronic Infarcted Pig Heart. Journal of Cardiovascular Translational Research. 2014; 7(2): 232-241. doi: 10.1007/s12265-013-9518-4

Published
2024-06-17
How to Cite
Guan, J.-Q., Zang, C.-B., Li, J.-C., Chen, F.-F., Wang, Y.-H., Zhou, G.-D., Liu, Y., & Cao, Y.-L. (2024). Hepatocyte growth factor and insulin-like growth factor-1 were used to repair bone-cartilage defects in bone marrow mesenchymal stem cells in a rabbit model of postmenopausal. Molecular & Cellular Biomechanics, 21, 72. https://doi.org/10.62617/mcb.v21.72
Issue
Vol. 21 (2024)
Section
Article

Copyright (c) 2024 Jia-Qi Guan, Chuan-Bo Zang, Jun-Cen Li, Fei-Fan Chen, Ya-Hui Wang, Guang-Dong Zhou, Yu Liu, Yi-Lin Cao

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