WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of the ligamentum flavum through Hedgehog-Gli1 signaling

Chao Sun,Qinghong Ma,Jian Yin,Han Zhang,Xinhui Liu

doi:10.1038/s12276-021-00636-5

Abstract

Ongoing chronic fibrosis and hypertrophy of the ligamentum flavum (LF) is an important cause of lumbar spinal canal stenosis (LSCS). Our previous work showed that WNT1-inducible signaling pathway protein 1 (WISP-1) is a critical driver of LF fibrosis. However, the potential mechanism has not been explored. Here, we found that Gli1 was upregulated in hypertrophic LF tissues and required for fibrogenesis in fibroblasts. Moreover, mechanical stretching increased the expression of WISP-1 in LF fibroblasts. Furthermore, WISP-1 induced fibrogenesis in vitro through the Hedgehog-Gli1 pathway. This conclusion was supported by the fact that WISP-1 activated the Hedgehog-Gli1 pathway in LF fibroblasts and that cyclopamine attenuated the effect of WISP-1-induced fibrogenesis. WISP-1 also promoted the transition of fibroblasts into myofibroblasts via the Hedgehog pathway. Importantly, a hypertrophic LF rabbit model induced by mechanical stress also showed pathological changes in fibrosis and elevated expression of WISP-1, Gli1, and α-SMA. Therapeutic administration of cyclopamine reduced collagen expression, fibroblast proliferation, and myofibroblast differentiation and ameliorated fibrosis in the mechanical stress-induced rabbit model. Collectively, our findings show mechanical stress/WISP-1/Hedgehog signaling as a new fibrotic axis contributing to LF hypertrophy and identify Hedgehog signaling as a therapeutic target for the prevention and treatment of LF fibrosis.

Highlights

Lumbar spinal canal stenosis (LSCS) occurs mainly in the elderly population with symptoms of back and/or leg pain, numbness, and intermittent claudication.[1]
Hedgehog-Gli[1] signaling is activated in hypertrophic ligamentum flavum (LF) tissue and highly associated with LF fibrosis To elucidate the molecular pathway involved in LF fibrosis, we focused on Hedgehog-Gli[1] signaling, as this pathway was previously reported to be involved in fibrosis in various diseases.[20]
In this study, we confirmed, for the first time, that mechanical stress induces WNT1-inducible signaling pathway protein 1 (WISP-1) expression in LF cells obtained from LF tissues of LSCS patients

Summary

Introduction

Lumbar spinal canal stenosis (LSCS) occurs mainly in the elderly population with symptoms of back and/or leg pain, numbness, and intermittent claudication.[1] The development of LSCS is attributable to several pathogenic factors, such as disc protrusion, facet joint degeneration, and ligamentum flavum (LF) hypertrophy. LF hypertrophy is considered an important factor in the development of LSCS.[2]. The hypertrophic LF shows fibrotic changes characterized by a loss of elastic fibers and an increase in collagen fiber content.[5,6] Fibrosis is a very common pathophysiological change in many chronic diseases.[7] Fibrosis is the main pathological feature of LF hypertrophy.[5,8] the detailed pathological mechanism of LF fibrosis is not clear

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Results

Conclusion