본문 바로가기
KERD
논문KCI 등재

Decorin: a potential therapeutic candidate for ligamentum flavum hypertrophy by antagonizing TGF-β1

Liu Yang|Xu Tao|Wang Shanxi|Qu Yunkun|Fang Xuan|Ding Qing|Zhao Hongqi|Yu Xiaojun|Lu Rui|Jing Shaoze|Liu Chaoxu|Wu Hua
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2023.12|Experimental and Molecular Medicine|제55권 |pp. 1413-1423|DOI 10.1038/s12276-023-01023-y

2

조회

0

다운로드

1

인용

0

참고문헌

주제분류생화학

초록

Ligamentum flavum hypertrophy (LFH) is the main physiological and pathological mechanism of lumbar spinal canal stenosis (LSCS). The specific mechanism for LFH has not been completely clarified. In this study, bioinformatic analysis, human ligamentum flavum (LF) tissues collection and analysis, and in vitro and in vivo experiments were conducted to explore the effect of decorin (DCN) on LFH pathogenesis. Here, we found that TGF-β1, collagen I, collagen III, α-SMA and fibronectin were significantly upregulated in hypertrophic LF samples. The DCN protein expression in hypertrophic LF samples was higher than that in non-LFH samples, but the difference was not significant. DCN inhibited the expression of TGF-β1-induced fibrosis-associated proteins in human LF cells, including collagen I, collagen III, α-SMA, and fibronectin. ELISAs showed that TGF-β1 can upregulate PINP and PIIINP in the cell supernatant, and this effect was inhibited after DCN administration. Mechanistic studies revealed that DCN suppressed TGF-β1-induced fibrosis by blocking the TGF-β1/SMAD3 signaling pathway. In addition, DCN ameliorated mechanical stress-induced LFH in vivo. In summary, our findings indicated that DCN ameliorated mechanical stress-induced LFH by antagonizing the TGF-β1/SMAD3 signaling pathway in vitro and in vivo. These findings imply that DCN is a potential therapeutic candidate for ligamentum flavum hypertrophy.

Abstract

Ligamentum flavum hypertrophy (LFH) is the main physiological and pathological mechanism of lumbar spinal canal stenosis (LSCS). The specific mechanism for LFH has not been completely clarified. In this study, bioinformatic analysis, human ligamentum flavum (LF) tissues collection and analysis, and in vitro and in vivo experiments were conducted to explore the effect of decorin (DCN) on LFH pathogenesis. Here, we found that TGF-β1, collagen I, collagen III, α-SMA and fibronectin were significantly upregulated in hypertrophic LF samples. The DCN protein expression in hypertrophic LF samples was higher than that in non-LFH samples, but the difference was not significant. DCN inhibited the expression of TGF-β1-induced fibrosis-associated proteins in human LF cells, including collagen I, collagen III, α-SMA, and fibronectin. ELISAs showed that TGF-β1 can upregulate PINP and PIIINP in the cell supernatant, and this effect was inhibited after DCN administration. Mechanistic studies revealed that DCN suppressed TGF-β1-induced fibrosis by blocking the TGF-β1/SMAD3 signaling pathway. In addition, DCN ameliorated mechanical stress-induced LFH in vivo. In summary, our findings indicated that DCN ameliorated mechanical stress-induced LFH by antagonizing the TGF-β1/SMAD3 signaling pathway in vitro and in vivo. These findings imply that DCN is a potential therapeutic candidate for ligamentum flavum hypertrophy.

참고문헌 (52)

  1. Spivak, J. M, "Degenerative lumbar spinal stenosis", J. Bone Jt. Surg. Am, 80, pp.1053~1066 (1998)
  2. Beamer, Y. B., "Hypertrophied ligamentum flavum. Clinical and surgical significance", Arch. Surg, 106, pp.289~292 (1973)
  3. Grenier, N., "Normal and degenerative posterior spinal structures : MR imaging", Radiology, 165, pp.517~525 (1987)
  4. Yabe, Y., "Chondrogenic and fibrotic process in the ligamentum flavum of patients with lumbar spinal canal stenosis", Spine(Philos. Pa 1976), 40, pp.429~435 (2015)
  5. Olszewski, A. D., "The anatomy of the human lumbar ligamentum flavum. New observations and their surgical importance", Spine(Philos. Pa 1976), 21, pp.2307~2312 (1996)
  6. Viejo-Fuertes, D., "Morphologic and histologic study of the ligamentum flavum in the thoraco-lumbar region", Surg. Radio. Anat, 20, pp.171~176 (1998)
  7. Zhong, Z. M., "Hypertrophy of ligamentum flavum in lumbar spine stenosis associated with the increased expression of connective tissue growth factor", J. Orthop. Res, 29, pp.1592~1597 (2011)
  8. Honsawek, S., "Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with increased bFGF expression", Int. Orthop, 37, pp.1387~1392 (2013)
  9. Kosaka, H., "Pathomechanism of loss of elasticity and hypertrophy of lumbar ligamentum flavum in elderly patients with lumbar spinal canal stenosis", Spine(Philos. Pa 1976), 32, pp.2805~2811 (2007)
  10. Park, J. B., "The increased expression of matrix metalloproteinases associated with elastin degradation and fibrosis of the ligamentum flavum in patients with lumbar spinal stenosis", Clin. Orthop. Surg, 1, pp.81~89 (2009)
  11. Nakatani, T., "Mechanical stretching force promotes collagen synthesis by cultured cells from human ligamentum flavum via transforming growth factorbeta1", J. Orthop. Res, 20, pp.1380~1386 (2002)
  12. Sun Chao, "WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of the ligamentum flavum through Hedgehog-Gli1 signaling", Experimental and Molecular Medicine, 53, pp.1~12 (2021), 생화학분자생물학회[DOI]
  13. Sun, C., "Leptin-induced inflammation by activating IL-6 expression contributes to the fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis", Biosci. Rep, 38, pp.R20171214~ (2018)
  14. Sun, C., "Ligamentum flavum fibrosis and hypertrophy : molecular pathways, cellular mechanisms, and future directions", FASEB J, 34, pp.9854~9868 (2020)
  15. Amudong, A., "Hypertrophy of the ligamentum flavum and expression of transforming growth factor beta", J. Int. Med. Res, 45, pp.2036~2041 (2017)
  16. Löhr, M., "Hypertrophy of the lumbar ligamentum flavum is associated with inflammation-related TGF-β expression", Acta Neurochir, 153, pp.134~141 (2011)
  17. Park, J. B., "Quantitative analysis of transforming growth factor-beta 1 in ligamentum flavum of lumbar spinal stenosis and disc herniation", Spine(Philos. Pa 1976), 26, pp.E492~E495 (2001)
  18. Rispoli, R., "Morphology and TGF-beta1 concentration analysis of ligamentum flavum in patients with lumbar canal stenosis and lumbar disc herniation", Neuroradiol. J, 23, pp.347~353 (2010)
  19. Gubbiotti, M. A., "Decorin interacting network : A comprehensive analysis of decorin-binding partners and their versatile functions", Matrix Biol, 5, pp.7~21 (2016)
  20. Yamaguchi, Y., "Negative regulation of transforming growth factor-beta by the proteoglycan decorin", Nature, 346, pp.281~284 (1990)
  21. Border, W. A., "Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease", Nature, 360, pp.361~364 (1992)
  22. Alan, C., "Protective effect of decorin on acute ischaemia-reperfusion injury in the rat kidney", Arch. Med. Sci, 7, pp.211~216 (2011)
  23. Ding, Q., "The preventive effect of decorin on epidural fibrosis and epidural adhesions after laminectomy", Front Pharm, 12, pp.774316~ (2021)
  24. Schneider, M., "Decorin—an antagonist of TGF-β in astrocytes of the optic nerve", Int J. Mol. Sci, 22, pp.7660~ (2021)
  25. Tang, X., "The effect of anti-inflammatory and antifibrotic agents on fibroblasts obtained from arthrofibrotic tissue : an in vitro and in vivo study", Bone Jt. Res, 7, pp.213~222 (2018)
  26. Zhang, Z., "Recombinant human decorin inhibits cell proliferation and downregulates TGF-β1 production in hypertrophic scar fibroblasts", Burns, 33, pp.634~641 (2007)
  27. Zhu, J., "Relationships between TGF-beta-1, myostatin, and decorin : Implications for skeletal muscle fibrosis", J. Biol. Chem, 282, pp.25852~25863 (2007)
  28. Liu, R., "Why weight? Modelling sample and observational level variability improves power in RNA-seq analyses", Nucleic Acids Res, 43, pp.e97~ (2015)
  29. Wu, T., "clusterProfiler 4.0: A universal enrichment tool for interpreting omics data", Innov. (Camb. ), 2, pp.100141~ (2021)
  30. Wang, B., "The increased motion of lumbar induces ligamentum flavum hypertrophy in a rat model", Bmc Musculoskel Dis, 22, pp.334~ (2021)
  31. Sairyo, K., "Lumbar ligamentum flavum hypertrophy is due to accumulation of inflammation-related scar tissue", Spine(Philos. Pa 1976), 32, pp.E340~E347 (2007)
  32. Yabe, Y., "Decreased elastic fibers and increased proteoglycans in the ligamentum flavum of patients with lumbar spinal canal stenosis", J. Orthop. Res, 34, pp.1241~1247 (2016)
  33. Devanand Hulmani, "Morphological Changes in the Ligamentum Flavum in Degenerative Lumbar Canal Stenosis: A Prospective, Comparative Study", Asian Spine Journal, 14(6), pp.773~781 (2020), 대한척추외과학회[DOI]
  34. Jezek, J., "The role of vascularization on changes in ligamentum flavum mechanical properties and development of hypertrophy in patients with lumbar spinal stenosis", Spine J, 20, pp.1125~1133 (2020)
  35. Liu Chunlei, "Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling", Experimental and Molecular Medicine, 54, pp.1~14 (2022), 생화학분자생물학회[DOI]
  36. Ye, S., "CCN5 Reduces Ligamentum Flavum Hypertrophy by Modulating the TGF-β Pathway", J. Orthop. Res, 37, pp.2634~2644 (2019)
  37. Fukushima, K., "The use of an antifibrosis agent to improve muscle recovery after laceration", Am. J. Sport Med, 29, pp.394~402 (2001)
  38. Jiang, N., "Anti-fibrotic effect of decorin in peritoneal dialysis and PDassociated peritonitis", Ebiomedicine, 52, pp.102661~ (2020)
  39. Kolb, M., "Proteoglycans decorin and biglycan differentially modulate TGFbeta-mediated fibrotic responses in the lung", Am. J. Physiol. -Lung C, 208, pp.L1327~L1334 (2001)
  40. Yang, K., "EGF contributes to hypertrophy of human ligamentum flavum via the TGF-β1", Smad3 signaling pathway, 2022, pp.19, 1510~1518
  41. Zheng, Z., "CRLF1 is a key regulator in the ligamentum flavum hypertrophy", Front Cell Dev. Biol, 8, pp.858~ (2020)
  42. Liu, C., "CHPF regulates the aggressive phenotypes of hepatocellular carcinoma cells via the modulation of the decorin and TGF-β pathways", Cancers, 13, pp.1261~ (2021)
  43. Isaka, Y., "Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney", Nat. Med, 2, pp.418~423 (1996)
  44. Yan, J., "Decorin GAG Synthesis and TGF-β Signaling Mediate Ox-LDL–Induced Mineralization of Human Vascular Smooth Muscle Cells", Arterioscl Throm Vas, 31, pp.608~615 (2011)
  45. Baghy, K., "Decorin-TGFbeta axis in hepatic fibrosis and cirrhosis", J. Histochem Cytochem, 60, pp.262~268 (2012)
  46. Branton, M. H., "TGF-beta and fibrosis", Microbes Infect, 1, pp.1349~1365 (1999)
  47. Scott, P. G., "Fibroblasts from post-burn hypertrophic scar tissue synthesize less decorin than normal dermal fibroblasts", Clin. Sci, 94, pp.541~547 (1998)
  48. Honardoust, D., "Small leucine-rich proteoglycans, decorin and fibromodulin, are reduced in postburn hypertrophic scar", Wound Repair Regen, 19, pp.368~378 (2011)
  49. Plaas, A. H., "Proteoglycan metabolism during repair of the ruptured medial collateral ligament in skeletally mature rabbits", Arch. Biochem Biophys, 374, pp.35~41 (2000)
  50. Pakshir, P., "The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication", Matrix Biol, 68–69, pp.81~93 (2018)
  51. Weiskirchen, R., "Organ and tissue fibrosis : Molecular signals, cellular mechanisms and translational implications", Mol. Asp. Med, 65, pp.2~15 (2019)
  52. Gurtner, G. C., "Wound repair and regeneration", Nature, 453, pp.314~321 (2008)

관련 논문AI추천

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signalingAo Xiang, Huang Minjun, Lian Zhengnan, Li Chenglong, Li Peng, Liu Chunlei, Liu Jie, Wang Liang, Zhang Zhongmin생화학분자생물학회 · Experimental and Molecular Medicine2022 · 제54권 Noncoding RNA as a crucial epigenetic modulator in the degeneration of the ligamentum flavumLin Jialiang, Li Weishi, Sun Zhuoran, Tian Shuo, Wang Longjie, Wu Zhenquan, Xiang Qian, Zhao Yongzhao생화학분자생물학회 · Experimental and Molecular Medicine2024 · 제56권 Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-β-mediated Smad2/3 phosphorylationChen Fan, Chen Shunlun, Guo Xingyu, Huang Yuming, Jiang Guowei, Lei Linchuan, Liu Caijun, Liu Hui, Li Zemin, Wang Hua, Wang Jianru, Zhao Zhuoyang, Zheng Zhaomin생화학분자생물학회 · Experimental and Molecular Medicine2022 · 제54권 Combination of Runx2 and BMP2 increases conversion of human ligamentum flavum cells into osteoblastic cells김성곤, 김신윤, 김재룡, 김현남, 민우기, 박병철, 정재환, 최제용생화학분자생물학회 · BMB Reports2011 · 제44권 제7호Relaxin Modulates the Expression of MMPs and TIMPs in Fibroblasts of Patients with Carpal Tunnel Syndrome강호, 강영미, 문성환, 이환모, 최윤락연세대학교의과대학 · Yonsei Medical Journal2017 · 제58권 제2호Rebalancing SMAD7/SMAD3 Signaling Reduces Adhesion Formation during Flexor Tendon HealingJia Jiameng, Jiang Ke, Li Yuling, Xiang Chao, Xiong Yan한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2023 · 제33권 제3호

이 간행물의 다른 논문 (225건)

Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics김성영, Han Yeaeunpp. 1-12Grave-to-cradle: human embryonic lineage tracing from the postmortem bodyKu Eu Jeong, Choi Seock Hwan, Choi Yujin Angelina, Oh Ji Wonpp. 13-21Chromatin and noncoding RNA-mediated mechanisms of gastric tumorigenesisKim Tae-Hee, Loe Adrian Kwan Ho, Zhu Lexinpp. 22-31TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cellsCha Hyuk-Jin, Kim Yun-Jeong, Go Young-Hyun, 정호창, Kwon Eun-Ji, Kim Seong-Min, Cheong Hyun Sub, Kim Wantae, Shin Hyoung Doo, Lee Haeseungpp. 32-42ZBTB7A suppresses glioblastoma tumorigenesis through the transcriptional repression of EPB41L5Nam Hae Yun, 김성학, 김승후, 최경철, Park Seung-Ho, Song Ji-Hye, Jeong Ji-Hoon, Kim Hyunhee, Jeong Minseok, Kong Min-Jeong, Son Jihyun, Jeong Ji-Eunpp. 43-54
원문 보기