Welcome to visit Zhongnan Medical Journal Press Series journal website!

Home Articles Vol 37,2024 No.7 Detail

Status of etiology and pathogenesis of lumbar ligamentum flavum hypertrophy

Published on Aug. 05, 2024Total Views: 1243 times Total Downloads: 302 times Download Mobile

Author: MAO Jianwei 1 YAN Weiping 2 ZHANG Weiping 2 YANG Chen 2 LI Jingzhou 2 QIANG Tianming 2 DUAN Wenshuai 1

Affiliation: 1. Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, China 2. The Fourth Department of Spinal Bone, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou 730050, China

Keywords: Ligamentum flavum hypertrophy Fibrosis Etiology Pathogenesis

DOI: 10.12173/j.issn.1004-4337.202401171

Reference: Mao JW, Yan WP, Zhang WP, Yang C, Li JZ, Qiang TM, Duan WS. Status of etiology and pathogenesis of lumbar ligamentum flavum hypertrophy[J]. Journal of Mathematical Medicine, 2024, 37(7): 534-542. DOI: 10.12173/j.issn.1004-4337.202401171[Article in Chinese]

  • Abstract
  • Full-text
  • References
Abstract

Ligamentum flavum is one of the important supporting ligaments in spinal canal to maintain the stability of spinal structure. Lumbar ligamentum flavum hypertrophy (LFH) is a chronic pathological process that changes the nature and structure of the ligamentum flavum due to aging, obesity, mechanical stress, inflammation and other reasons. The hypertrophic ligamentum flavum compresses the spinal cord or nerve roots and produces a series of symptoms, such as lower back pain or lower limb pain and numbness, which is an important cause of lumbar spinal stenosis. There are many reports on the etiology and mechanism of LFH, but there is a lack of corresponding summary and induction. From the perspective of etiology and pathological mechanism, this paper reviews the relevant literature about lumbar LFH in recent 5 years, discusses and summarizes the etiology and mechanism of LFH, and expounds the research status of LFH and targeted molecular intervention in LFH.

Full-text
Please download the PDF version to read the full text: download
References

1.Ma C, Qi X, Wei YF, et al. Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles[J]. Bioact Mater, 2022, 19: 139-154. DOI: 10.1016/j.bioactmat.2022.03.042.

2.Yücetaş ŞC, Çakir T. Decreased catalase expression is associated with ligamentum flavum hypertrophy due to lumbar spinal canal stenosis[J]. Medicine (Baltimore), 2019, 98(15): e15192. DOI: 10.1097/MD.0000000000015192.

3.Shemesh S, Laks A, Cohen I, et al. Diabetes mellitus and poor glycemic control are associated with a higher risk of lumbar spinal stenosis: an analysis of a large nationwide database[J]. Spine (Phila Pa 1976), 2023. DOI: 10.1097/BRS.0000000000004900.

4.Kim CS, Kim H, Kim S, et al. Prevalence of and factors associated with stenotic thoracic ligamentum flavum hypertrophy[J]. Reg Anesth Pain Med, 2023. DOI: 10.1136/rapm-2023-104692.

5.Chick CN, Inoue T, Mori N, et al. LC-MS/MS analysis of elastin crosslinker desmosines and microscopic evaluation in clinical samples of patients with hypertrophy of ligamentum flavum[J]. Bioorg Med Chem, 2023, 82: 117216. DOI: 10.1016/j.bmc.2023.117216.

6.Zhang B, Chen G, Yang X, et al. Dysregulation of micrornas in hypertrophy and ossification of ligamentum flavum: new advances, challenges, and potential directions[J]. Front Genet, 2021, 12: 641575. DOI: 10.3389/fgene.2021.641575.

7.Wáng YX, Wáng JQ, Káplár Z. Increased low back pain prevalence in females than in males after menopause age: evidences based on synthetic literature review[J]. Quant Imaging Med Surg, 2016, 6(2): 199-206. DOI: 10.21037/qims.2016.04.06.

8.Chen MH, Hu CK, Chen PR, et al. Dose-dependent regulation of cell proliferation and collagen degradation by estradiol on ligamentum flavum[J]. BMC Musculoskelet Disord, 2014, 15: 238. DOI: 10.1186/1471-2474-15-238.

9.Takashima H, Takebayashi T, Yoshimoto M, et al. The difference in gender affects the pathogenesis of ligamentum flavum hypertrophy[J]. Spine Surg Relat Res, 2018, 2(4): 263-269. DOI: 10.22603/ssrr.2017-0069.

10.Sun C, Ma Q, Yin J, et al. WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of  the ligamentum flavum through Hedgehog-Gli1 signaling[J]. Exp Mol Med, 2021, 53(6): 1068-1079. DOI: 10.1038/s12276-021-00636-5.

11.Yabe Y, Hagiwara Y, Tsuchiya M, et al. Factors associated with thickening of the ligamentum flavum on magnetic resonance imaging in patients with lumbar spinal canal stenosis[J]. Spine (Phila Pa 1976), 2022, 47(14): 1036-1041. DOI: 10.1097/BRS.0000000000004341.

12.Kolte VS, Khambatta S, Ambiye MV. Thickness of the ligamentum flavum: correlation with age and its asymmetry-an magnetic resonance imaging study[J]. Asian Spine J, 2015, 9(2): 245-253. DOI: 10.4184/asj.2015.9.2.245.

13.Li P, Liu C, Qian L, et al. miR-10396b-3p inhibits mechanical stress-induced ligamentum flavum hypertrophy by targeting IL-11[J]. FASEB J, 2021, 35(6): e21676. DOI: 10.1096/fj.202100169RR.

14.Sun C, Zhang H, Wang X, et al. Ligamentum flavum fibrosis and hypertrophy: molecular pathways, cellular mechanisms, and future directions[J]. FASEB J, 2020, 34(8): 9854-9868. DOI: 10.1096/fj.202000635R.

15.Slater J, Kolber MJ, Schellhase KC, et al. The influence of exercise on perceived pain and disability in patients with lumbar spinal stenosis: a systematic review of randomized controlled trials[J]. Am J Lifestyle Med, 2015, 10(2): 136-147. DOI: 10.1177/1559827615571510.

16.Seki S, Iwasaki M, Makino H, et al. Association of ligamentum flavum hypertrophy with adolescent idiopathic scoliosis progression-comparative microarray gene expression analysis[J]. Int J Mol Sci, 2022, 23(9): 5038. DOI: 10.3390/ijms23095038.

17.Zhang B, Yuan L, Chen G, et al. Deciphering obesity-related gene clusters unearths SOCS3 immune infiltrates and 5mC/m6A modifiers in ossification of ligamentum flavum pathogenesis[J]. Front Endocrinol (Lausanne), 2022, 13: 861567. DOI: 10.3389/fendo.2022.861567.

18.Kim J, Kwon WK, Cho H, et al. Ligamentum flavum hypertrophy significantly contributes to the severity of neurogenic intermittent claudication in patients with lumbar spinal canal stenosis[J]. Medicine (Baltimore), 2022, 101(36): e30171. DOI: 10.1097/MD.0000000000030171.

19.Kim KT, Cho DC, Sung JK, et al. Changes in HbA1c levels and body mass index after successful decompression surgery in patients with type 2 diabetes mellitus and lumbar spinal stenosis: results of a 2-year follow-up study[J]. Spine J, 2017, 17(2): 203-210. DOI: 10.1016/j.spinee.2016.08.029.

20.Li P, Fei CS, Chen YL, et al. Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model[J]. Front Immunol, 2022, 13: 973799. DOI: 10.3389/fimmu.2022.973799.

21.Liu C, Li P, Ao X, et al. Clusterin negatively modulates mechanical stress-mediated ligamentum flavum  hypertrophy through TGF-beta1 signaling[J]. Exp Mol Med, 2022, 54(9): 1549-1562. DOI: 10.1038/s12276-022-00849-2.

22.Hori Y, Suzuki A, Hayashi K, et al. Long-term, time-course evaluation of ligamentum flavum hypertrophy induced by mechanical stress: an experimental animal study[J]. Spine (Phila Pa 1976), 2021, 46(9): E520-E527. DOI:10.1097/BRS.0000000000003832.

23.Liu C, Li P, Ao X, et al. Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling[J]. Exp Mol Med, 2022, 54(9): 1549-1562. DOI: 10.1038/s12276-022-00849-2.

24.Kwon WK, Ham CH, Choi H, et al. Elucidating the effect of mechanical stretch stress on the mechanism of ligamentum flavum hypertrophy: development of a novel in vitro multi-torsional stretch loading device[J]. PLoS One, 2022, 17(10): e275239. DOI: 10.1371/journal.pone.0275239.

25.Yan B, Huang M, Zeng C, et al. Locally produced IGF- 1 promotes hypertrophy of the ligamentum flavum via the mTORC1 signaling pathway[J]. Cell Physiol Biochem, 2018, 48(1): 293-303. DOI: 10.1159/000491729.

26.Morrow MR, Batchuluun B, Wu J, et al. Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia[J]. Cell Metab, 2022, 34(6): 919-936. DOI: 10.1016/j.cmet.2022.05.004.

27.Barreto J, Karathanasis SK, Remaley A, et al. Role of LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1) as a cardiovascular risk predictor: mechanistic insight and potential clinical use[J]. Arterioscler Thromb Vasc Biol, 2021, 41(1): 153-166. DOI: 10.1161/ATVBAHA.120.315421.

28.Nagai S, Hachiya K, Takeda H, et al. Impact of oxidized LDL/LOX-1 system on ligamentum flavum hypertrophy[J]. J Orthop Sci, 2023, 28(3): 669-676. DOI: 10.1016/j.jos. 2022.01.006.

29.Gu Y, Yu W, Qi M, et al. Identification and validation of hub genes and pathways associated with mitochondrial dysfunction in hypertrophy of ligamentum flavum[J]. Front Genet, 2023, 14: 1117416. DOI: 10.3389/fgene.2023. 1117416.

30.Endo T, Takahata M, Fujita R, et al. Strong relationship between dyslipidemia and the ectopic ossification of the spinal ligaments[J]. Sci Rep, 2022, 12(1): 22617. DOI: 10.1038/s41598-022-27136-4.

31.Kakadiya G, Saindane K, Soni Y, et al. Diabetes mellitus and the development of lumbar canal stenosis: is there any relevance[J]. Asian Spine J, 2022, 16(3): 326-333. DOI: 10.31616/asj.2020.0566.

32.Shemesh S, Sidon E, Kaisler E, et al. Diabetes mellitus is associated with increased elastin fiber loss in ligamentum flavum of patients with lumbar spinal canal stenosis: results of a pilot histological study[J]. Eur Spine J, 2018, 27(7): 1614-1622. DOI: 10.1007/s00586-017-5315-0.

33.Maruf MH, Suzuki A, Hayashi K, et al. Increased advanced glycation end products in hypertrophied ligamentum flavum of diabetes mellitus patients[J]. Spine J, 2019, 19(10): 1739-1745. DOI: 10.1016/j.spinee.2019.06.001.

34.Luo J, Huang L, Chen Z, et al. Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis[J]. J Orthop Res, 2017, 35(5): 1058-1066. DOI: 10.1002/jor.23302.

35.Kim SI, Ha KY, Lee JW, et al. Prevalence and related clinical factors of thoracic ossification of the ligamentum flavum-a computed tomography-based cross-sectional study[J]. Spine J, 2018, 18(4): 551-557. DOI: 10.1016/j.spinee.2017.08.240.

36.Lee CY, Wu MH, Huang TJ, et al. Hypertrophic ligamentum flavum in lumbar spine stenosis is associated with the increased expression of secreted protein acidic and rich in cysteine[J]. Global Spine J, 2022: 1270889650. DOI: 10.1177/21925682221138766.

37.Yabe Y, Hagiwara Y, Ando A, et al. Chondrogenic and fibrotic process in the ligamentum flavum of patients with lumbar spinal canal stenosis[J]. Spine (Phila Pa 1976), 2015, 40(7): 429-435. DOI: 10.1097/BRS.0000000000000795.

38.Lu QL, Zheng ZX, Ye YH, et al. Macrophage migration inhibitory factor takes part in the lumbar ligamentum flavum hypertrophy[J]. Mol Med Rep, 2022, 26(3): 289. DOI: 10.3892/mmr.2022.12805.

39.Habibi H, Suzuki A, Hayashi K, et al. Expression and function of fibroblast growth factor 1 in the hypertrophied ligamentum flavum of lumbar spinal stenosis[J]. J Orthop Sci, 2022, 27(2): 299-307. DOI: 10.1016/j.jos.2021.01.004.

40.Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications[J]. Mol Aspects Med, 2019, 65: 2-15. DOI: 10.1016/j.mam.2018.06.003.

41.Dolivo DM, Larson SA, Dominko T. Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis[J]. Cell Mol Life Sci, 2018, 75(20): 3663-3681. DOI: 10.1007/s00018-018-2880-2.

42.Amudong A, Muheremu A, Abudourexiti T. Hypertrophy of the ligamentum flavum and expression of transforming growth factor beta[J]. J Int Med Res, 2017, 45(6): 2036-2041. DOI: 10.1177/0300060517711308.

43.Hirabayashi S. Ossification of the ligamentum flavum[J]. Spine Surg Relat Res, 2017, 1(4): 158-163. DOI:10.22603/ssrr.1.2016-0031.

44.Ye S, Kwon WK, Bae T, et al. CCN5 reduces ligamentum flavum hypertrophy by modulating the TGF-β pathway[J]. J Orthop Res, 2019, 37(12): 2634-2644. DOI: 10.1002/jor.24425.

45.Sziksz E, Pap D, Lippai R, et al. Fibrosis related inflammatory mediators: role of the IL-10 cytokine family[J]. Mediators Inflamm, 2015, 2015: 764641. DOI: 10.1155/2015/764641.

46.Sutovsky J, Benco M, Sutovska M, et al. Cytokine and chemokine profile changes in patients with lower segment lumbar degenerative spondylolisthesis[J]. Int J Surg, 2017, 43: 163-170. DOI: 10.1016/j.ijsu.2017.06.024.

47.Wang B, Gao C, Zhang P, et al. The increased motion of lumbar induces ligamentum flavum hypertrophy in a rat model[J]. BMC Musculoskelet Disord, 2021, 22(1): 334. DOI: 10.1186/s12891-021-04203-x.

48.Li P, Liu C, Qian L, et al. miR-10396b-3p inhibits mechanical stress-induced ligamentum flavum hypertrophy by targeting IL-11[J]. FASEB J, 2021, 35(6): e21676. DOI: 10.1096/fj.202100169RR.

49.Han S, Jang IT. Prevalence and distribution of incidental thoracic disc herniation, and thoracic hypertrophied ligamentum flavum in patients with back or leg pain: a magnetic resonance imaging-based cross-sectional study[J]. World Neurosurgery, 2018, 120: e517-e524. DOI: 10.1016/j.wneu.2018.08.118.

50.Burt KG, Viola DC, Lisiewski LE, et al. An in vivo model of ligamentum flavum hypertrophy from early-stage inflammation to fibrosis[J]. JOR Spine, 2023, 6(3): e1260. DOI: 10.1002/jsp2.1260.

51.Nagai S, Hachiya K, Takeda H, et al. Impact of oxidized LDL/LOX-1 system on ligamentum flavum hypertrophy[J]. J Orthop Sci, 2023, 28(3): 669-676. DOI: 10.1016/j.jos. 2022.01.006.

52.Nasto LA, Robinson AR, Ngo K, et al. Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration[J]. J Orthop Res, 2013, 31(7): 1150-1157. DOI: 10.1002/jor.22320.

53.Gu Y, Hu J, Wang C, et al. Smurf1 facilitates oxidative stress and fibrosis of ligamentum flavum by promoting Nrf2 ubiquitination and degradation[J]. Mediators Inflamm, 2023, 2023: 1164147. DOI: 10.1155/2023/1164147.

54.Ansari MY, Ahmad N, Haqqi TM. Oxidative stress and inflammation in osteoarthritis pathogenesis: role of  polyphenols[J]. Biomed Pharmacother, 2020, 129: 110452. DOI: 10.1016/j.biopha.2020.110452.

55.Hong JY, Kim H, Lee J, et al. Harpagophytum procumbens inhibits iron overload-induced oxidative stress through activation of Nrf2 signaling in a rat model of lumbar spinal stenosis[J]. Oxid Med Cell Longev, 2022, 2022: 3472443. DOI:10.1155/2022/3472443.

56.Hsu YC, Chuang HC, Tsai KL, et al. Administration of N-acetylcysteine to regress the fibrogenic and proinflammatory effects of oxidative stress in hypertrophic ligamentum flavum cells[J]. Oxid Med Cell Longev, 2022, 2022: 1380353. DOI: 10.1155/2022/1380353.

57.Ito K, Kise H, Suzuki S, et al. Potential involvement of oxidative stress in ligamentum flavum hypertrophy[J]. J Clin Med, 2023, 12(3): 808. DOI: 10.3390/jcm12030808.

58.Suzuki S, Fujita N, Hosogane N, et al. Excessive reactive oxygen species are therapeutic targets for intervertebral disc degeneration[J]. Arthritis Res Ther, 2015, 17: 316. DOI: 10.1186/s13075-015-0834-8.

59.Chuang HC, Tsai KL, Tsai KJ, et al. Oxidative stress mediates age-related hypertrophy of ligamentum flavum by inducing inflammation, fibrosis, and apoptosis through activating Akt and MAPK pathways[J]. Aging (Albany NY), 2020, 12(23): 24168-24183. DOI: 10.18632/aging.104105.

60.George KM, Hernandez NS, Breton J, et al. Lumbar ligamentum flavum burden: evaluating the role of ATTRwt amyloid deposition in ligamentum flavum thickness at all lumbar levels[J]. Clin Neurol Neurosurg, 2021, 206: 106708. DOI: 10.1016/j.clineuro.2021.106708.

61.Yang K, Chen Y, Xiang X, et al. EGF contributes to hypertrophy of human ligamentum flavum via the tgf-beta1/smad3 signaling pathway[J]. Int J Med Sci, 2022, 19(10): 1510-1518. DOI: 10.7150/ijms.76077.

62.Xu YQ, Zhang ZH, Zheng YF, et al. MicroRNA-221 regulates hypertrophy of ligamentum flavum in lumbar spinal stenosis by targeting TIMP-2[J]. Spine (Phila Pa 1976), 2016, 41(4): 275-282. DOI: 10.1097/BRS.0000000000001226.

63.Shin HK, Seo KJ, Lee JY, et al. GSK-3β and β-catenin signaling pathway is involved in myofibroblast transition of ligamentum flavum in lumbar spinal stenosis patients[J]. Spine (Phila Pa 1976), 2023, 48(20): 1472-1479. DOI:10.1097/BRS.0000000000004770.

64.Sun C, Ma Q, Yin J, et al. WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of the ligamentum flavum through Hedgehog-Gli1 signaling[J]. Exp Mol Med, 2021, 53(6): 1068-1079. DOI: 10.1038/s12276-021-00636-5.

65.Duan Y, Li J, Qiu S, et al. TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum[J]. J Transl Med, 2022, 20(1): 468. DOI: 10.1186/s12967-022-03677-0.

Popular papers
Last 6 months