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 ɑ-SMA.
Therapeutic administration of cyclopamine reduced collagen expression,
fibroblast proliferation, myofibroblast differentiation and ameliorated
LF fibrosis in mechanical stress-induced rabbit model.