Biomarkers related to hypertrophy of the ligamentum flavum: a systematic review of the literature

William Mualem Department of General Surgery, Temple University, Philadelphia, Pennsylvania;
Department of Neurosurgery, MedStar Georgetown University Hospital, Washington, DC

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Jiaqi Liu Georgetown University School of Medicine, Washington, DC; and
Department of Neurosurgery, MedStar Georgetown University Hospital, Washington, DC

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Alan Balu Georgetown University School of Medicine, Washington, DC; and
Department of Neurosurgery, MedStar Georgetown University Hospital, Washington, DC

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Kelsi Chesney Department of Neurosurgery, MedStar Georgetown University Hospital, Washington, DC

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M. Nathan Nair Department of Neurosurgery, MedStar Georgetown University Hospital, Washington, DC

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OBJECTIVE

Spinal stenosis is one of the most common spinal disorders in the elderly. Hypertrophy of the ligamentum flavum (HLF) can contribute to spinal stenosis. The current literature suggests that various biomarkers may play important roles in the pathogenesis of HLF. However, the connection between these biomarkers and the development of HLF is still not well understood. This systematic review aims to explore the current literature on biomarkers related to the development of HLF.

METHODS

A literature search was conducted using PubMed, Embase, Web of Science, and Cochrane Library. The search strategy looked for the titles, abstracts, and keywords of studies that contained a combination of the following phrases: "ligamentum flavum OR yellow ligament," "biomarkers," and "hypertrophy." Recorded data included study design, demographic characteristics (number of patients of each gender and mean age), study period, country where the study was conducted, biomarkers, and diagnostic modalities used. Risk of bias was assessed using the Newcastle-Ottawa Scale for case-control studies.

RESULTS

The authors identified 39 studies. After screening, 26 full-text original articles assessing one or more biomarkers related to HLF were included. The included studies were conducted over a 22-year period. The most popular biomarkers studied, in order of frequency reported, were collagen types I and III (n = 10), transforming growth factor β (TGF-β) (n = 8), and interleukin (IL)–6 (n = 6). The authors found that mechanical stretching forces, tissue inhibitor of metalloproteinases 2 (TIMP-2) induction, and TGF-β were associated with increased amounts of collagen I and III. IL-6 expression was increased by microRNA-21, as well as by leptin, through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway.

CONCLUSIONS

Biomarkers such as TGF-β, IL-6, and collagen I and III have been consistently correlated with the development of HLF. However, the pathogenesis of HLF remains unclear due to the heterogeneity of the studies, patient populations, and research at the molecular level. Further studies are necessary to better characterize the pathogenesis of HLF and provide a more comprehensive understanding of how these biomarkers may aid in the diagnosis and treatment of HLF.

ABBREVIATIONS

ANGPTL-2 = angiopoietin-like protein 2; bFGF = basic fibroblast growth factor; HLF = hypertrophy of the ligamentum flavum; IGF-1 = insulin-like growth factor 1; IL = interleukin; miR = microRNA; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; TGF-β = transforming growth factor β; TIMP-2 = tissue inhibitor of metalloproteinases 2; TNF-α = tumor necrosis factor α; VEGF = vascular endothelial growth factor.
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Illustration from Murata et al. (pp 9–16). © Shizumasa Murata, published with permission.

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