TGF-β1, in association with the increased expression of connective tissue growth factor, induce the hypertrophy of the ligamentum flavum through the p38 MAPK pathway

Abstract

Hypertrophy of the ligamentum flavum (LF) is one of the key pathomechanisms of lumbar spinal stenosis (LSS). Transforming growth factor (TGF)-β1 is abundantly expressed in hypertrophied degenerative LF tissues from LSS. However, the molecular mechanisms underling the association between TGF-β1 and LF hypertrophy have not yet been fully elucidated. In this study, we investigated the important role of the mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of LSS by analyzing the expression of connective tissue growth factor (CTGF) and extracellular matrix (ECM) components (collagen I and collagen III) in TGF-β1-treated LF cells. Cell growth assay revealed that TGF-β1, in association with CTGF, enhanced the the proliferation of LF cells, and we found that TGF-β1 also elevated CTGF expression and subsequently enhanced the mRNA expression of collagen I and collagen III. The increased mRNA expression levels of CTGF, collagen I and collagen III were abolished by p38 inhibitors. Both immunofluorescence imaging and western blot analysis of p38 and p-p38 revealed the increased expression and phosphorylation of p38. Silencing the expression of p38 by siRNA in LF cells decreased the protein expression of p38, p-p38 and CTGF, as well as the mRNA expression of CTGF, collagen I and collagen III. Taken together, our findings indicate that TGF-β1, in association with the increased expression of CTGF, contribute to the homeostasis of the ECM and to the hypertrophy of LF through the p38 MAPK pathway.

CCN5 Reduces Ligamentum Flavum Hypertrophy by Modulating the TGF‐β Pathway

“…Research on the pathophysiology of LFH has been of great interest to spine specialists, and the majority of specialists have suggested that tissue inflammation, angiogenesis, and fibrosis lead to LFH . Although the development of LFH cannot be described by a single pathway or a single biomechanical change, the relationships between LFH and several key factors, including transforming growth factor‐β1 (TGF‐β1), angiopoietin‐like protein 2 (ANGPTL2), vascular endothelial growth factor (VEGF), and several other cytokines have been investigated . It is widely known that among these cytokines, TGF‐β1 is the main component of LFH that leads to LSCS.…”

“…It is widely known that among these cytokines, TGF‐β1 is the main component of LFH that leads to LSCS. Several studies have elucidated the key links of TGF‐β to inflammation, angiogenesis, extracellular matrix (ECM) regulation, and myofibroblast transdifferentiation leading to LFH. However, convincing evidence is still lacking regarding whether inhibition of the TGF‐β pathway can actually prevent LFH.…”

Locally Produced IGF-1 Promotes Hypertrophy of the Ligamentum Flavum via the mTORC1 Signaling Pathway

“…Some studies suggested that chronic inflammation induced by mechanical stress was a vital impact factor for HLF [11,12]. It is believed that when suffering from increased mechanical stress, the ligamentum flavum is constantly damaged, causing a local release of inflammationrelated factors, such as TNF-α, TGF-b1, IL-1 and IL-6, which can stimulate LF fibrosis and contribute to the pathological process of HLF [12,[33][34][35][36]. Although inflammatory factors are believed to play a crucial role in HLF [5,11,[37][38][39][40], the molecular basis for LF tissue fibrosis remains unclear.…”

Influence on mitogen-activated protein kinases as a new direction of connective tissue growth regulation

“…Об аналогичных наблюдениях в отношении гипертрофированной желтой связки сообщили [24], фибробластов оболочки глаза [25].…”