Melatonin Protects Intervertebral Disc from Degeneration by Improving Cell Survival and Function via Activation of the ERK1/2 Signaling Pathway

Abstract

Melatonin, a neuroendocrine hormone secreted by the pineal body, has a positive effect on intervertebral disc degeneration. The present study is aimed at investigating the biological role of melatonin in intervertebral disc degeneration and its underlying mechanism. A human nucleus pulposus cell (NPC) line was exposed to melatonin at different concentrations. Cell proliferation was measured by CCK-8 assay. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to measure the protein expression of indicated genes. A rabbit model of intervertebral disc degeneration was established to detect the role and mechanism of melatonin on intervertebral disc degeneration. Our study showed that melatonin promoted NPC viability and inhibited cell arrest. Furthermore, melatonin treatment led to the upregulation of collagen II and aggrecan and downregulation of collagen X. Moreover, melatonin significantly elevated the activity of the ERK signaling pathway. Inhibition of the ERK1/2 signals reversed the role of melatonin in the regulation of NPCs both in vitro and in vivo. Melatonin increased NPC viability through inhibition of cell cycle arrest and apoptosis. Moreover, melatonin promoted the secretion of functional factors influencing the nucleus pulposus cell physiology and retarded cell degeneration. Our results suggest that melatonin activated the ERK1/2 signaling pathway, thereby affecting the biological properties of the intervertebral disc degeneration.

Melatonin Promotes the Proliferation of Chicken Sertoli Cells by Activating the ERK/Inhibin Alpha Subunit Signaling Pathway

“…Our results indicated that melatonin significantly increased the level of p-ERK1/2 and the inhibition of the ERK1/2 signaling pathway reversed melatonin-induced Sertoli cell proliferation and down-regulated the expression of CCND1, PCNA, and INHA. Recently study has shown that melatonin promotes viability in human nucleus pulposus cells (NPC) and activates the ERK signaling pathway, but inhibition of the ERK signaling pathway reverses the effects of melatonin on NPC [33]. Melatonin can also promote osteoblast differentiation through the ERK signaling pathway [34].…”

Melatonin prevents the binding of vascular endothelial growth factor to its receptor and promotes the expression of extracellular matrix‑associated genes in nucleus pulposus cells

“…Recently, the protective effect of melatonin in IDD was also reported. Ge et al ( 14 ) revealed that the melatonin was able to upregulate the expression of collagen-II and aggrecan via elevating the activity of the ERK signaling pathway in a rabbit model of IDD. Melatonin also ameliorated IDD via mitophagy induction and apoptosis inhibition ( 16 ).…”

“…Melatonin is an endogenous molecule released from the pineal gland that has a role in the regulation of the circadian rhythm and anti-oxidative stress and has an anti-inflammatory effect ( 14 , 15 ). Recent studies have reported that melatonin may protect IVDs from degeneration by improving cell survival and mitophagy induction ( 14 , 16 ). In addition, melatonin has been reported to exert a potential anti-angiogenic effect ( 17 ).…”

Melatonin: A potential therapeutic agent against COVID-19

“…Melatonin suppressed the TLR2/MyD88/p-ERK pathway to reduce IL-2, IL-6, IL-10, IL-17, IFN-γ, and tumor necrosis factor (TFN)-α production, thus subsiding inflammation in Helicobacter pylori-infected mice (87). These effects were mediated by melatonin membrane receptors, MT1 and MT2, as anti-inflammatory effects were reduced by blocking these receptors (88,89). Melatonin blocks the secondary inflammatory cytokine storm caused by damage-associated molecular patterns (DAMPs) of mitochondrial origin.…”

“…During inflammation, but not during normal conditions, melatonin is able to downregulate TLR2, TLR4, and TLR9 expression, or inhibit their downstream pathways (153) Luo et al (153) reported that melatonin suppresses the TLR2/MyD88/p-ERK pathway to reduce IL-2, IL-6, IL-10, IL-17, IFN-γ, and TFN-α production, thus subsiding inflammation in H. pyloriinfected mice. Similarly, melatonin reduced the innate immune response by inhibiting the TLR4/ MAPK/NF-κB pathway through its membrane receptors MT1 and MT2, since its antiinflammatory effects were reduced by blocking these receptors (88,89). Through inhibition of the ERK1/2 and AKT pathways, melatonin suppresses TLR9-mediated innate immune responses without involving receptors MT1 and MT2 (154) .…”