1 | INTRODUCTION
Generally, lumbar spinal canal stenosis (LSCS) mainly occurs in the
aging population. Owing to the compression of the spinal cord, nerve
roots, or cauda equine, it often shows symptoms of low back or/and leg
pain, numbness, and intermittent claudication (Schizas et al., 2010).
The development of LSCS is attributable to several pathogenic factors
such as disc protrusion, facet joints degeneration, and ligamentum
flavum (LF) hypertrophy. Most importantly, LF hypertrophy is considered
as the important factor contributing to the development of LSCS with the
age (Sakai et al., 2017).
Anatomically, the LF covers the posterior part of the dura sac, acting
in limiting the range of intervertebral movement and protecting the
spinal cord (Schroeder et al., 2016; Ammendolia et al., 2019). The
normal LF is an elastic structure rich in elastic fibers. By contrast,
the hypertrophic LF shows fibrotic changes characterized by the loss of
elastic fibers and an increase of collagen fibers (Yan et al., 2018). As
is known, fibrosis is the very common pathophysiological change of many
chronic diseases (Rockey et al., 2015). Similarly, it is noteworthy that
fibrosis is also proved to be the main pathological feature of LF
hypertrophy (Yan et al., 2018; Sun et al., 2020). However, the detailed
pathomechanism of LF fibrosis is not quite clear.
The CCN family is composed of six matrix proteins mainly functioning in
the extracellular microenvironment between cells and plays important
roles in extracellular matrix (ECM) regulation (Murphy-Ullrich & Sage
et al., 2014; Perbal et al., 2019). Among them, WISP-1, namely CCN4, has
been recently studied most extensively and involved in the fibrotic
process in a variety of organ systems (Yang et al., 2020; Königshoff et
al., 2009). Previous work of our group showed that WISP1 was highly
expressed in hypertrophied LF and closely associated with LF fibrosis
(Sun et al., 2017). However, little is known about the mechanism by
which WISP-1 is activated and the downstream mechanism of WISP-1 in
driving activation of fibroblasts in the context of LF fibrosis has
never been explored. The results presented in this study not only deepen
the understanding of the role and mechanism of WISP-1 in LF fibrosis but
also offer a theoretical basis for developing new drugs for LF
hypertrophy.