Matrix metalloproteinase promotes elastic fiber degradation in ligamentum flavum degeneration

Abstract

Ligamentum flavum (LF) hypertrophy in lumbar spinal canal stenosis (LSCS) is characterized by a loss of elastic fibers and fibrosis. Chronic inflammation is thought to be responsible for the histological change but the mechanism underlying elastic fiber degradation remains unclear. Given that matrix metalloproteinase (MMP)-2 and -9 have elastolytic activity and are partly regulated by inflammatory cytokines such as interleukin (IL)-6, in this study, we investigated whether MMPs mediate LF degeneration using 52 LF samples obtained during lumbar surgery, including 31 LSCS and 21 control specimens. We confirmed by histological analysis that the LSCS samples exhibited severe degenerative changes compared with the controls. We found that MMP-2 was upregulated in LF tissue from patients with LSCS at the mRNA and protein levels, whereas MMP-9 expression did not differ between the two groups. The MMP-2 level was positively correlated with LF thickness and negatively correlated with the area occupied by elastic fibers. IL-6 mRNA expression was also increased in LF tissue from patients with LSCS and positively correlated with that of MMP-2. Signal transducer and activator of transcription (STAT)3, a component of the IL-6 signaling pathway, was activated in hypertrophied LF tissues. Our in vitro experiments using fibroblasts from LF tissue revealed that IL-6 increased MMP-2 expression, secretion, and activation via induction of STAT3 signaling, and this effect was reversed by STAT3 inhibitor treatment. Moreover, elastin degradation was promoted by IL-6 stimulation in LF fibroblast culture medium. These results indicate that MMP-2 induction by IL-6/STAT3 signaling in LF fibroblasts can degrade elastic fibers, leading to LF degeneration in LSCS.

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

“…6). The LF cells in the LSS group displayed high elastin degradation, which is consistent with previous studies [37][38][39]. Notably, the morphological features of the LF cells in the 3D spheroid model were more similar to those of the LFH tissue, including random arrangement and cell-cell clustering, than those of the 2D-culture cells.…”

Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

“…Pathological changes in the ligamentum flavum (LF) can be defined as a process of chronic progressive aberrations in the nature and structure of ligamentous tissues, characterized by increased thickness, reduced elasticity, local calcification, or aggravated ossification of LF fibroblasts, which may cause spinal stenosis and severe myelopathy, radiculopathy, or both (Yayama et al, 2007;Yabe et al, 2015;Sugimoto et al, 2018). Clinically, hypertrophy of ligamentum flavum (HLF) and ossification of ligamentum flavum (OLF) are the main pathological categories, while calcification of ligamentum flavum (CLF) is extremely rare (Giulioni et al, 2007).…”

Human collagen alpha-2 type I stimulates collagen synthesis, wound healing, and elastin production in normal human dermal fibroblasts (HDFs)

“…According to previous study, collagen peptides inhibited the expression of metalloproteinases (MMP1 and MMP3) release while simultaneously increasing elastin synthesis ( 7 , 37 ). Matrix metalloproteinases (MMP1 and MMP3), the major collagenases in human, which were induced by ultraviolet irradiation (UV)/ sun exposure and natural skin aging, mediate the degradation of fibrillar type I collagen and elastic fiber ( 38 - 40 ). In contrast, treatment of the collagen peptides or derivatives such as a hCOL1A2 (SMM) provides the anti-skin aging effect through collagen expression/activation (collagen chain trimerization) and activation of TGF-β signal pathway ( 37 ).…”