WISP-1 induced by mechanical stress contributes to the fibrosis
and hypertrophy of ligamentum flavum via the Hedgehog-Gli1 signaling
Chao Sun, Qinghong Ma, Jian Yin, Han Zhang, Xinhui
Liu*
Department of Spine Surgery, The Affiliated Jiangning Hospital with
Nanjing Medical University, Nanjing, Jiangsu 211100, China
*Corresponding author. Department of Spine Surgery,
The Affiliated Jiangning Hospital with Nanjing Medical University,
Nanjing, Jiangsu 211100, China.
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.
Conclusion and Implications: Our study showed the mechanical
stress/WISP-1/ Hedgehog signaling as a new fibrotic axis contributing to
the LF hypertrophy and identified Hedgehog signaling as a therapeutic
target for the prevention and treatment of LF fibrosis.
KEYWORDS : Aging; Ligamentum
flavum; WISP-1; Gli1; Hypertrophy; Fibrosis