title: Salubrinal Suppresses IL-17-Induced Upregulation of MMP-13 and Extracellular Matrix Degradation Through the NF-kB Pathway in Human Nucleus Pulposus Cells.
abstract: Matrix metalloproteinase 13 (MMP-13) plays an important role in the process of pro-inflammatory cytokine-induced intervertebral disc degeneration (IDD). This study examined the effect of IL-17 on the regulation of MMP-13 and the extracellular matrix (ECM) in the intervertebral disc (IVD). We then examined whether salubrinal, a known inhibitor of eIF2α dephosphorylation, inhibited the IL-17-induced changes mentioned above. Furthermore, we demonstrated a potential therapeutic role for salubrinal in alleviating the chronic inflammatory-dependent degenerative state commonly observed in IDD. After inflammatory distress with IL-17, RT-PCR and western blot were employed to investigate the expression of MMP-13, collagen type II (COL2A1), collagen type I (COL1A1), and aggrecan (ACAN) in nucleus pulpous (NP) tissue. Activation of the NF-kB pathway was measured by western blot and immunocytochemistry following IL-17 treatment. We also examine the level of eIF2α phosphorylation after IL-17 treatment with or without salubrinal. Then, we investigated interactions of the NF-kB pathway to eIF2α phosphorylation. Moreover, we employed salubrinal and a specific inhibitor of NF-kB (BAY11-7082) to evaluate their effects on IL-17-driven regulation of MMP-13 and the ECM, as well as on the activation of NF-kB. The results showed that IL-17 increased the production of MMP-13 and decreased expression of COL2A1 and ACAN via the NF-kB pathway. Either IL-17 or salubrinal increased the level of eIF2α phosphorylation, but the effects of BAY11-7082 on the level of p-eIF2α were not detectable. BAY11-7082 and salubrinal significantly suppressed IL-17-driven intervertebral disc degeneration. Furthermore, salubrinal produced stronger effects than BAY11-7082. These results imply the potential involvement of IL-17 in IDD through activation of NF-kB signaling, which successively upregulated the expression of MMP-13 and led to the degradation of the ECM. Furthermore, salubrinal can inhibit this process through inhibition of NF-kB activation that is not directly linked to eIF2α phosphorylation, suggesting a potential therapeutic role in IDD.
authors: Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China.|The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China.
authors: Zhixiao
authors: Z
authors: Yao
authors: Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China.
authors: Lin
authors: L
authors: Nie
authors: Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China.
authors: Yunpeng
authors: Y
authors: Zhao
authors: Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China.
authors: Yuanqiang
authors: Y
authors: Zhang
authors: Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China.
authors: Yi
authors: Y
authors: Liu
authors: Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China.
authors: Jingkun
authors: J
authors: Li
authors: Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China. chengleiyx@126.com.
authors: Lei
authors: L
authors: Cheng
mesh_terms: D053674:Aggrecans / Q000032:analysis; D002934:Cinnamates / Q000494:pharmacology* / Q000627:therapeutic use; D024042:Collagen Type I / Q000032:analysis; D024043:Collagen Type II / Q000032:analysis; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D000070614:Nucleus Pulposus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D053674:Aggrecans; D002934:Cinnamates; D024042:Collagen Type I; D024043:Collagen Type II; D015852:Eukaryotic Initiation Factor-2; D020381:Interleukin-17; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; C496827:salubrinal; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D013890:Thiourea
keywords: IL-17; MMP-13; NF-kB; extracellular matrix; intervertebral disc degeneration (IDD); salubrinal