Abstract
BackgroundIntervertebral disc (IVD) degeneration is a major cause of low back pain (LBP). Following disc injury, nerve growth factor (NGF) concentrations rise in IVDs, and anti-NGF therapy has been shown to attenuate LBP in humans. Increased levels of tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) in degenerative IVDs and in in vitro studies suggest that these factors promote NGF production. However, whether these factors regulate NGF in vivo remains unclear. Thus, we studied NGF regulation in a mouse model of IVD injury.MethodsAfter inducing IVD injury, we examined mRNA levels of Tnfa, Tgfb, and Ngf in IVDs from control and IVD-injured mice across 7 days. To do this, we used magnetic cell separation to isolate CD11b ( +) (macrophage-rich) and CD11b (-) (IVD cell-rich) cell fractions from injured IVDs. To study the effect of TNF-α on Ngf expression, we examined Ngf expression in injured IVDs from C57BL/6 J and Tnfa-knockout (KO) mice (C57BL/6 J background). To study the effect of TGF-β on Ngf expression, C57/BL6J mice were given an intraperitoneal injection of either the TGF-β inhibitor SB431542 or DMSO solution (vehicle) one and two days before harvesting IVDs.ResultsmRNA expression of Tnfa, Tgfb, and Ngf was significantly increased in injured IVDs. Tnfa was predominantly expressed in the CD11b ( +) fraction, and Tgfb in the CD11b (-) fraction. Ngf expression was comparable between CD11b ( +) and CD11b (-) fractions, and between wild-type and Tnfa-KO mice at post-injury day (PID) 1, 3, and 7. SB431542 suppressed TGF-β-mediated Ngf expression and NGF production in vitro. Further, administration of SB431542 significantly reduced Ngf expression in IVDs such that levels were below those observed in vehicle-treated animals at PID3 and PID7.ConclusionA TGF-β inhibitor reduced Ngf expression in a mouse model of IVD injury, suggesting that TGF-β may regulate NGF expression in vivo.
Highlights
Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP)
We previously reported that transforming growth factor-β (TGF-β) stimulates nerve growth factor (NGF) production in mouse IVD cells in vitro [6]
Effect of TGF‐β inhibitor, SB431542, on NGF expression and production in IVD cell culture To determine whether the TGF‐β inhibitor, SB431542, inhibits Ngf expression and NGF production in IVD cells, we examined the effect of SB431542 on TGF‐β-mediated Ngf expression and NGF production by IVD cells isolated from five mice
Summary
Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP). Increased levels of tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) in degenerative IVDs and in in vitro studies suggest that these factors promote NGF production. Whether these factors regulate NGF in vivo remains unclear. A major cause of LBP is the degeneration of intervertebral discs (IVDs) [3, 4]. We previously reported that TGF-β stimulates NGF production in mouse IVD cells in vitro [6]. Accumulating evidence from in vitro studies suggests that TNF-α and TGF-β contribute to the regulation of NGF during IVD degeneration. Whether TNF-α and TGF-β regulate NGF expression in vivo remains unclear
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