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      Necrostatin-1 Attenuates Trauma-Induced Mouse Osteoarthritis and IL-1β Induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes.

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          Abstract

          Necrostatin-1 (Nec-1) is a specific small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1) that specifically inhibits phosphorylation of RIPK1. RIPK1 regulates inflammation and cell death by interacting with receptor-interacting serine/threonine protein kinases 3(RIPK3). We hypothesized that Nec-1 may have anti-inflammatory efficacy in patients with osteoarthritis (OA), as the pathophysiology of OA involves the activation of inflammation-related signaling pathways and apoptosis. In this study, we explored the effects of Nec-1 on interleukin (IL)-1β-induced inflammation in mouse chondrocytes and the destabilised medial meniscus (DMM) mouse model. Inhibiting RIPK1 with Nec-1 dramatically suppressed catabolism both in vivo and in vitro, but did not inhibit changes in subchondral bone. Nec-1 abolished the in vitro increases in matrix metalloproteinase (MMP) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTs5) expression induced by IL-1β. However, adding high-mobility group box 1 (HMGB1) partially abrogated this effect, indicating the essential role of HMGB1 and Nec-1 in the protection of primary chondrocytes. Furthermore, Nec-1 decreased the expression of Toll-like receptor 4 (TLR4) and stromal cell-derived factor-1 (SDF-1), and attenuated the interaction between TLR4 and HMGB1. Western blot results suggested that Nec-1 significantly suppressed IL-1β-induced NF-κB transcriptional activity, but not MAPK pathway. Micro-computed tomography, immunohistochemical staining, and Safranin O/Fast Green staining were used in vivo to assess the degree of destruction of OA cartilage. The results show that NEC-1 can significantly reduce the degree of destruction of OA cartilage. Therefore, Nec-1 may be a novel therapeutic candidate to treat OA.

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          Most cited references33

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          Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

          Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
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            Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints.

            Data on the incidence of symptomatic osteoarthritis (OA) are scarce. We estimated incidence of clinical hip, knee and hand OA, and studied the effect of prevalent OA on joint-specific incident OA. SIDIAP contains primary care records for>5 million people from Catalonia (Spain). Participants aged ≥40 years with an incident diagnosis of knee, hip or hand OA between 2006 and 2010 were identified using International Classification of Diseases (ICD)-10 codes. Incidence rates and female-to-male rate ratios (RRs) for each joint site were calculated. Age, gender and body mass index-adjusted HR for future joint-specific OA according to prevalent OA at other sites were estimated using Cox regression. 3 266 826 participants were studied for a median of 4.45 years. Knee and hip OA rates increased continuously with age, and female-to-male RRs were highest at age 70-75 years. In contrast, female hand OA risk peaked at age 60-64 years, and corresponding female-to-male RR was highest at age 50-55 years. Adjusted HR for prevalent knee OA on risk of hip OA was 1.35 (99% CI 1.28 to 1.43); prevalent hip OA on incident knee OA: HR 1.15 (1.08 to 1.23). Prevalent hand OA predicted incident knee and hip OA: HR 1.20 (1.14 to 1.26) and 1.23 (1.13 to 1.34), respectively. The effect of age is greatest in the elderly for knee and hip OA, but around the menopause for hand OA. OA clusters within individuals, with higher risk of incident knee and hip disease from prevalent lower limb and hand OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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              Pathogenesis and management of pain in osteoarthritis.

              The term osteoarthritis describes a common, age-related, heterogeneous group of disorders characterised pathologically by focal areas of loss of articular cartilage in synovial joints, associated with varying degrees of osteophyte formation, subchondral bone change, and synovitis. Joint damage is caused by a mixture of systemic factors that predispose to the disease, and local mechanical factors that dictate its distribution and severity. Various genetic abnormalities have been described, but most sporadic osteoarthritis probably depends on minor contributions from several genetic loci. Osteoarthritic joint damage may be associated with clinical problems, but the severity of joint disease is only weakly related to that of the clinical problem. For this reason the associations and pathogenesis of pain are in as much need of investigation as joint damage. Subchondral bone and synovium may be responsible for nociceptive stimuli, and peripheral neuronal sensitisation is an important feature, and can result in normal activities (such as walking) causing pain. Central pain sensitisation can also occur, and psychosocial factors are important determinants of pain severity. We present a stepwise approach to the management of osteoarthritis.
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                Author and article information

                Journal
                Front Pharmacol
                Frontiers in pharmacology
                Frontiers Media SA
                1663-9812
                1663-9812
                2018
                : 9
                Affiliations
                [1 ] Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
                [2 ] Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, United States.
                [3 ] Department of Orthopaedic Surgery, Henan Provincial People's Hospital, Zhengzhou, China.
                Article
                10.3389/fphar.2018.01378
                6277802
                30542285
                a310e97e-5d3c-467e-a333-c002ebb7b49f
                History

                apoptosis,chondrocyte,inflammation,necroptosis,necrostatin-1,osteoarthritis

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