Abstract
Hypertrophy of the ligamentum flavum (HLF) is one of the common causes of lumbar spinal stenosis (LSS). The key molecules and mechanisms responsible for HLF remain unclear. Here, we used an integrated transcriptome and proteomics analysis of human ligamentum flavum (LF), and subsequent immunohistochemistry and real-time PCR assays, to show upregulation of CRLF1 to be the dominant response to HLF. TGF-β1 significantly increased mRNA expression of CRLF1 through SMAD3 pathway. CRLF1 enhanced LF fibrosis via ERK signaling pathway at the post-transcriptional level and was required for the pro-fibrotic effect of TGF-β1. Knockdown of CRLF1 was shown here to reduce fibrosis caused by inflammatory cytokines and mechanical stress. Furthermore, we found that bipedal standing posture can cause HLF and upregulation of CRLF1 expression in mice LF. Overexpression of CRLF1 was indicated to cause HLF in vivo, whereas CRLF1 knockdown impeded the formation of HLF in bipedal standing mice. These results revealed a crucial role of CRLF1 in LF hypertrophy. We propose that inhibition of CRLF1 is a potential therapeutic strategy to treat HLF.
Highlights
Lumbar spinal stenosis (LSS) is the most common spinal disorder in elderly patients (Backstrom et al, 2011; Altun and Yuksel, 2017)
We found increased myofibroblasts in Hypertrophy of the ligamentum flavum (HLF) (Figure 2B), and the number of cytokine receptorlike factor 1 (CRLF1)-positive cells was positively correlated with the number of myofibroblasts (Figure 2D)
These findings indicated that ligamentum flavum (LF) myofibroblasts-derived CRLF1 may act as an independent regulator which contribute to the pathological process of ligamentum flavum hypertrophy (LFH)
Summary
Lumbar spinal stenosis (LSS) is the most common spinal disorder in elderly patients (Backstrom et al, 2011; Altun and Yuksel, 2017). Previous studies have suggested that mechanical stress was the initial cause of HLF (Fukuyama et al, 1995; Nakatani et al, 2002) and could induce several cytokines espression in fibroblasts, such as transforming growth factor (TGF-β1) and IL-6 (Koyama and Aizawa, 2002; Nakatani et al, 2002; Jacobs et al, 2014) These cytokines have been reported to induce fibrosis in a variety of soft tissues (Mozaffarian et al, 2008; Diaz et al, 2009; Gonzalez et al, 2016; Li et al, 2019), the key cytokines and precise mechanism of the pathology of HLF
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