Abstract
Structural changes in nucleus pulposus cells induce intervertebral disc (IVD) degeneration as a consequence of cytokine generation, biochemical products, and changes in the local environment. We have previously shown that inflammatory cytokines induce murine IVD (mIVD) angiogenesis and macrophage migration. Although the physiological roles of thrombin, a known proinflammatory factor, are documented, its relationship to IVD degeneration remains largely unexplored. Thrombin mediates cellular responses via the activation of protease-activated receptors such as PAR1 which has been studied in numerous cell types, but not extensively in IVD cells. This study was designed to investigate the endogenous expression of thrombin, tissue factor, and PAR1 in cultured coccygeal mIVDs. Thrombin exclusively induced MCP-1 via the MAPK-ERK and PI3K-AKT pathways. MCP-1 produced by mIVDs induced macrophage migration and thrombin treatment increased MMP-3 production to induce mIVD degeneration. These effects of thrombin on mIVDs were abrogated by a PAR1 inhibitor and suggest that thrombin may be a novel factor capable of stimulating cytokine activity implicated in the regulation several aspects of mIVDs. Mechanisms governing mIVDs, which are regulated by thrombin/PAR1 signaling, require elucidation if our understanding of IVD degenerative mechanisms is to advance.
Highlights
We have previously shown that angiogenesis and macrophage cell migration play an important role in the degeneration of herniated discs by stimulating the inflammatory cytokines MCP-1, TNF-α, TNF-like weak inducer of apoptosis (TWEAK), and thymic stromal lymphoprotein (TSLP)[13]
We have reported that MCP-1 induced by thrombin treatment via the PI3K/AKT and MAPK-ERK pathways in the fracture healing process, influenced MCP-1 macrophages to migrate to the sites of bone fracture[20]
Subsequent examinations using IHC staining for thrombin and tissue factor (TF) revealed thrombin was localized to the cytoplasm of AF and CEP cells in murine intervertebral disc (mIVD)
Summary
We have previously shown that angiogenesis and macrophage cell migration play an important role in the degeneration of herniated discs by stimulating the inflammatory cytokines MCP-1, TNF-α, TNF-like weak inducer of apoptosis (TWEAK), and thymic stromal lymphoprotein (TSLP)[13]. In primary human NP culture, thrombin modulated cytokine and chemokine expression, which increased the level of a variety of inflammatory mediators including CXCL1, IL-6, CXCL8, IL-27, and MCP-1. Thrombin stimulation induces MCP-1 expression in vascular endothelial cells, vascular smooth muscle, and retinal pigment epithelial cells, and it activates P38 MAPK, NF-κB signaling[16,17,18,19]. It is known that thrombin induces cytokine production in IVDs14, the precise function and mechanisms underpinning cell migration and IVD degeneration are still poorly understood. The purpose of the current study was to investigate the mechanisms for MCP-1 and MMP-3 induction after treatment with thrombin using coccygeal murine intervertebral disc (mIVD) tissue culture. Our aim is to explore whether thrombin/PAR1 signaling contributes to IVD degeneration
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