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

Abstract

Background and Purpose: The ongoing chronic fibrosis and hypertrophy of 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. This study was designed to explore the mechanism by which WISP-1 is activated and its underlying mechanisms in LF fibrosis. Experimental Approach: We studied the expression of Hedgehog-related proteins in human LF tissues. Cell viability, cell cycle, apoptosis rate and molecular mechanisms were evaluated in LF cells. Finally, the molecular mechanism was confirmed in vivo studies. Key Results: The results showed that Gli1 was upregulated in hypertrophic LF tissues and required for fibroblast viability and collagen expression in fibroblasts. Moreover, mechanical stretching increased WISP-1 expression in LF fibroblasts. Furthermore, WISP-1 induced fibrogenesis through Hedgehog-Gli1 pathway. This conclusion was supported by the fact that WISP-1 activated Hedgehog-Gli1 pathway in LF fibroblasts and cyclopamine attenuated the effect of WISP-1-induced fibrogenesis. WISP-1 also promoted the transition of fibroblasts into myofibroblasts via Hedgehog pathway. Importantly, hypertrophic LF rabbit model induced by mechanical stress also showed pathological change of fibrosis and more higher expression of WISP-1, Gli1 and a-SMA. Therapeutic administration of cyclopamine reduced collagen expression, fibroblast proliferation, myofibroblast differentiation and ameliorated LF fibrosis in mechanical stress-induced rabbit model. WISP-1 induced by mechanical stress contributes to the fibrosis and hypertrophy of ligamentum flavum via the Hedgehog-Gli1 signaling