Fibronectin fragment activation of ERK increasing integrin α₅ and β₁ subunit expression to degenerate nucleus pulposus cells

Abstract

Fibronectin fragments (Fn-f), which are the breakdown products of fibronectin, accumulate in the disc during degeneration and are proved to induce the degeneration of intervertebral disc. The goal of this investigation was to determine the functional role of integrin a 5 b 1 , extracellular signal-regulated kinase (ERK), and protein kinase C (PKC) in the process of Fn-f degeneration nucleus pulposus (NP) cells. We found that Fn-f (100 nM, 30 kDa) exposure led to degeneration of NP cells, up-regulation of integrin a 5 b 1 expression and phosphorylation of the ERK 1/2 . After the expression of integrin a 5 b 1 was silenced in NP cells, the phosphorylation of ERK 1/2 and the expression of MMP9, MMP13, and collagen II had no difference with control under the treatment of Fn-f. Finally, when the inhibitor of ERK 1/2 and the inhibitor of PKC were added into the medium of NP cells; we found these two inhibitors could eliminate the effect of Fn-f on NP cells. It is concluded that Fn-f had the potential to enhance the NP cell degeneration in a vicious circle. And the integrin a 5 b 1 subunit, ERK, and PKC were all included in this loop. ß

CCN2 Suppresses Catabolic Effects of Interleukin-1β through α5β1 and αVβ3 Integrins in Nucleus Pulposus Cells

“…Nonetheless, a strong positive correlation was observed between the expressions of these integrin subunits. Additionally, studies demonstrate the altered function of ␣5␤1 during degeneration (47,48). Le Maitre et al (47) showed that mechanotransduction through ␣5␤1 integrin was impaired in degenerate human NP cells, whereas Xia and Zhu (48) found that the fibronectin fragments that accumulate in the degenerative disc cause an increase in MMP-9 and -13 through ␣5␤1.…”

“…Additionally, studies demonstrate the altered function of ␣5␤1 during degeneration (47,48). Le Maitre et al (47) showed that mechanotransduction through ␣5␤1 integrin was impaired in degenerate human NP cells, whereas Xia and Zhu (48) found that the fibronectin fragments that accumulate in the degenerative disc cause an increase in MMP-9 and -13 through ␣5␤1. Moreover, it is important to note that along with altered integrin expression and function, CCN2 levels are also elevated during disc degeneration (11,22).…”

Detrimental Role for Human High Temperature Requirement Serine Protease A1 (HTRA1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration

“…5C) in degenerated discs. Moreover, the majority of amino-terminal fragments identified were found to be of a similar size (27)(28)(29) to the fragment identified within samples of HTRA1-digested human fibronectin (lane 1). Membranes were counterstained with Coomassie Blue to confirm equal protein loading (Fig.…”

“…Furthermore, fibronectin fragments were recently confirmed as being potent inducers of MMP expression in IVD cells, mediating their effects through activation of the MEK pathway (27). We therefore investigated whether inhibition of MEK could influence the actions of HTRA1 on IVD MMP expression.…”

The relation between cervical and thoracal disc herniations and multiple sclerosis plaques: a retrospective review

“…In MS patients spinal compressionat the disc may impair the normal water inflow and nutrient transportation process which leads to apoptosis and some conditions like cell adhesion, chemotaxis and opsonization [19]. Fibronectin which is the large glycoprotein portion of the nucleus pulposus plays a significant role in the organisation of ECM (Extracellular matrix) proteins [20]. Excess mechanical loading on the disc may fragmantate fibronectin [21].…”