title: Simvastatin Inhibits IL-1β-Induced Apoptosis and Extracellular Matrix Degradation by Suppressing the NF-kB and MAPK Pathways in Nucleus Pulposus Cells.
abstract: Statins are widely used hypocholesterolemic drugs that block the mevalonate pathway. Some studies have shown that statins may have the potential to inhibit intervertebral disk (IVD) degeneration (IDD). Interleukin (IL)-1β, a catabolic cytokine, is a key regulator of IDD. This study aimed to investigate the mechanism underlying the effect of simvastatin on IDD. The viability of nucleus pulposus (NP) cells was determined by the methyl-thiazolyl-tetrazolium (MTT) assay. The apoptosis of NP cells was measured by flow cytometric analysis, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and western blotting of relevant apoptotic proteins. The protein levels of catabolic factors and anabolic factors were determined by western blotting. The cells were stimulated with IL-1β in the absence or presence of simvastatin to investigate the effects on matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, type II collagen, and aggrecan expression. Our findings indicate that simvastatin considerably inhibited IL-1β-induced apoptosis in NP cells. We also found that simvastatin attenuated IL-1β-induced expression and MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 activities and also reduced the decrease in type II collagen and aggrecan expression. In addition, simvastatin considerably suppressed the nuclear translocation and activation of nuclear factor-kappa B (NF-KB) by inhibiting p65 phosphorylation and translocation and blocking inhibitor kB-α degradation. It also inhibited MAPK pathway activation by blocking c-Jun N-terminal kinase (JNK), p38, and ERK phosphorylation. The results of our study revealed that simvastatin is a potential agent for IDD prevention and treatment.
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Ji
authors.initials: J
authors.lastname: Tu
authors.affiliation: Wuhan Institute of Biological Products Co., Ltd., 430207, Wuhan, Hubei, People's Republic of China.
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Xinghuo
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Hua
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People's Republic of China. yang1971@sina.com.
authors.forename: Cao
authors.initials: C
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy* / Q000517:prevention & control; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000070614:Nucleus Pulposus / Q000166:cytology / Q000378:metabolism*; D012600:Scoliosis / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D019821:Simvastatin; D020928:Mitogen-Activated Protein Kinases
keywords: apoptosis; extracellular matrix degradation (EMD); intervertebral disk degeneration (IDD); mitogen-activated protein kinase (MAPK); nuclear factor-kappa B (NK-kB); simvastatin