Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the mitogen-activated protein kinase and Janus kinase 2/signal transducer and activator of transcription 3 pathways

Abstract

Obesity has been demonstrated to be involved in the progress of intervertebral disc degeneration (IDD). However, the associated mechanisms remain to be elucidated. The purpose the present study was to examine the effect of leptin on the expression of degeneration-associated genes in rat nucleus pulposus (NP) cells, and determine the possible mechanism. Normal NP cells, obtained from Sprague Dawley rats, were identified using immunocytochemistry for the expression of collagen II and CA125, and treated with leptin and/or interleukin (IL)-β. Subsequently, the mRNA expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, aggrecan and COL2A1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-q-PCR). Alcian staining and immunocytochemistry were used to examine the expression levels of proteoglycan and collagen II. The pathway activation was investigated using western blotting, and inhibitors of the pathways were used to reveal the effect of these pathways on the NP cells. The results of the RT-qPCR demonstrated that leptin alone upregulated the mRNA expression levels of MMP-1, MMP-13, ADAMTS-4, ADAMTS-5 and COL2A1. Synergy of leptin and IL-β was found in the increased expression levels of MMP-1, MMP-3 and ADAMTS-5. The leptin-treated NP cells exhibited decreased expression of collagen II. The mitrogen-activated protein kinase (MAPK) pathway (c-Jun-N-terminal kinase, phosphorylated extracellular signal-regulated kinase and p38), phosphatidylinositol 3-kinase (PI3K)/Akt pathway and Janus kinase (JAK)2/signal transducer and activator of transcription 3 pathway were all activated by leptin, however, inhibitors of all the pathways, with the exception of the PI3K/Akt pathway, reversed the expression levels of MMP-1 and MMP-13. These results suggested that leptin promoted catabolic metabolism in the rat NP cells via the MAPK and JAK2/STAT3 pathways, which may be the mechanism mediating the association between obesity and IDD.

Quinalizarin exerts an anti-tumour effect on lung cancer A549 cells by modulating the Akt, MAPK, STAT3 and p53 signalling pathways

“…p38 is activated by cell stress-induced signalling in response to various factors including toxic chemicals and oxidative stress (17). STAT3 activation also leads to increased cell proliferation, angiogenesis, multidrug resistance and decreased cell apoptosis (18). p53 activates target genes involved in cell cycle arrest, apoptosis, senescence, anti-angiogenesis and autophagy, thereby suppressing malignant tumour transformation and preserving genomic integrity (38).…”

“…Therefore, the MAPK in these signalling pathways are considered 'stress-activated protein kinases' in cellular signalling, inflammation, apoptosis and the pathogenesis of various diseases. The signal transducer and activator of transcription-3 (STAT3) signalling pathway has been shown to regulate the transcriptional activation of gene products that participate in cell proliferation and anti-apoptosis, such as cell cycle (cyclins and cyclin-dependent kinases, Cdks) and apoptotic regulators (Bcl-2 and Bad) (18). These findings indicate that the targeting of Akt, MAPK and STAT3 signalling pathways may be an important therapeutic target in novel cancer therapy.…”

Aloperine attenuates hydrogen peroxide-induced injury via anti-apoptotic activity and suppression of the nuclear factor-κB signaling pathway

“…Although numerous studies have investigated apoptosis, few studies have examined how oxidative stress results in nucleus pulposus cell apoptosis and intervertebral disc degeneration (10,13,14). Therefore, the current study used H 2 O 2 to establish an oxidative stress model in nucleus pulposus cells in order to identify the underlying mechanisms (15).…”

Resistin Promotes Intervertebral Disc Degeneration by Upregulation of ADAMTS-5 Through p38 MAPK Signaling Pathway

“…Recently, the pro-inflammatory and catabolic role of adipokines in cartilage has attracted increasingly significant attention [24][25][26][27]. Leptin has been observed to up-regulate MMPs and ADAMTS, as well as down-regulating aggrecan in NP cells [24,25]. Furthermore, resistin mediates the inflammatory activities of the chondrocytes, in which the expression levels of pro-inflammatory cytokines and chemokines are elevated [26,27].…”

“…Adipokines, secreted by adipose tissues, are found at increased concentration levels in obese individuals [21][22][23]. Some adipokines have been demonstrated to contribute to the pathogenesis of IDD and osteoarthritis, since they exert pro-inflammatory and catabolic role in cartillage chondrocytes and NP cells [21][22][23][24][25][26][27][28]. The adipokine resistin is a 12.5 kDa cysteine-rich polypeptide that belongs to a family of resistin-like molecules (RELMs) or "found in inflammatory zone" (FIZZ) molecules [29][30][31].…”