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.