Leptin-induced inflammation by activating IL-6 expression contributes to the fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis

Abstract

The ongoing chronic inflammation and subsequent fibrosis play an important role in ligamentum flavum (LF) fibrosis and hypertrophy in patients with lumbar spinal canal stenosis (LSCS). Leptin is a chronic inflammatory mediator and involved in the fibrotic process in multiple organ systems. The present study aimed to investigate the role of leptin in LF fibrosis and its related regulatory mechanisms. The LF specimens were obtained during the surgery from 12 patients with LSCS (LSCS group) and 12 control patients with lumbar disc herniation (LDH) group. The morphologic changes and fibrosis score of LF were assessed by Hematoxylin and eosin (H&E) and Masson’s trichrome staining respectively. The location and expression of leptin in LF tissues were determined. Then, the LF cells were cultured and exposed to recombinant human leptin (rhleptin). Collagen I and III were used as fibrosis markers and IL-6 was used as the inflammatory factor. As a result, the LF thickness and fibrosis score in the LSCS group were significantly higher than those in the LDH group (P<0.05). Leptin was detected in the hypertrophied LF and its expression was substantially increased in the LSCS group and positively correlated with LF thickness and fibrosis score (P<0.05). Moreover, our in vitro experiments revealed that rhleptin treated LF cells elevated the expression of collagen I and III. Finally, leptin administration induced IL-6 expression via nuclear factor-κB (NF-κB) pathway in LF cell (P<0.05). Our study demonstrated novel molecular events for leptin-induced inflammation in LF tissue by promoting IL-6 expression and thus might have potential implications for clarifying the mechanism underlying LF fibrosis and hypertrophy.

Development of an In Vitro 3D Model for Investigating Ligamentum Flavum Hypertrophy

“…Histological examination using H&E staining is a standard assessment in cytopathology used to study morphological changes, such as the arrangement of the LF structure and the severity of elastin degradation, i.e., loss, fragmentation and disorganization [36]. Compared with the nonhypertrophic LF tissue with a defined ECM orientation, the hypertrophied LF cells showed not only fragmented and disorganized fibers but also cell proliferation and cluster formation (Fig.…”

Molecular Relationships among Obesity, Inflammation and Intervertebral Disc Degeneration: Are Adipokines the Common Link?

“…Moreover, leptin can affect IVD adjacent tissues. In particular, leptin was described to be increased in lumbar spinal canal stenosis, to be positively correlated with ligamentum flavum hypertrophy and fibrosis, and to induce collagen I and III expressions, as well as IL-6 expression via NF-κB activation, in ligamentum flavum cells [44].…”

Intervertebral Disc and Adipokine Leptin—Loves Me, Loves Me Not

“…Sun et al studied the ligamenta flava— paired elastic ligaments running between adjacent laminae of the vertebral bodies (at level L4/5)—hence, not intervertebral disc directly [ 80 ]. They found higher leptin mRNA and protein expression in ligamenta flava of 12 patients with lumbar spinal canal stenosis compared to 12 patients with lumbar disc herniation (mean age 58 years and 63 years, respectively).…”

“…They found higher leptin mRNA and protein expression in ligamenta flava of 12 patients with lumbar spinal canal stenosis compared to 12 patients with lumbar disc herniation (mean age 58 years and 63 years, respectively). After leptin stimulation of cultured cells of ligamentum flavum, they demonstrated elevated expression of collagen type I and type III (as fibrosis markers), and IL-6, the latter via nuclear factor-κB pathway [ 80 ].…”