RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis

Jhun, JooYeon; Lee, Jun Young; Kim, Seyoung; Ryu, Jaeyoon; Kwon, Ji Ye; Na, Hyun Sik; Jung, Kyoung-Sim; Moon, Su‐Jin; Cho, Mi‐La; Min, Jun‐Ki

doi:10.1186/s12967-019-1809-3

Cited by 40 publications

(26 citation statements)

References 32 publications

(43 reference statements)

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“…Bone erosion worsened in the placebo group over the study duration, with little change in the GSK2982772 group, but one patient in the GSK29822772 group, who showed a large improvement, may have contributed to much of the mean difference between treatment groups. Alternatively, this finding may support other studies that have suggested a potential role for RIPK1 inhibition in the suppression of osteoclastogenesis [ 22 , 44 ].…”

Section: Discussionsupporting

confidence: 87%

“…RIPK1-mediated necroptosis has also been implicated in increased cytokine production and inflammatory diseases [ 19 – 21 ]. Inhibition of RIPK1 blocked necroptosis, suppressed osteoclastogenesis, reduced synovial expression of proinflammatory cytokines, and decreased arthritis progression in a collagen-induced mouse model of RA [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis

et al. 2021

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Background Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). Methods Patients with moderate to severe RA who had received ≥12 weeks’ stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. Results A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. Conclusions These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. Trial registration ClinicalTrials.gov Identifier: NCT02858492. Registered 8 August 2016.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis

et al. 2021

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“…The key regulators of necroptosis, RIPK1, RIPK3 and MLKL were potently increased in the synovium of a collagen-induced arthritis mouse model [83], indicating that necroptosis might be involved in the pathogenesis of RA. RIPK1 inhibitor Nec-1 significantly decreased the expression of these key regulators and suppressed the expression of IL-17, IL-1β, IL-6 and TNFα in the mouse model [84]. Therefore, inhibiting RIPK1 might be a novel therapeutic approach for the treatment of RA.…”

Section: Necroptosis In Rheumatoid Arthritismentioning

confidence: 98%

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Chen

Garssen

et al. 2019

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Necroptosis, or regulated necrosis, is an important type of programmed cell death in addition to apoptosis. Necroptosis induction leads to cell membrane disruption, inflammation and vascularization. It plays important roles in various pathological processes, including neurodegeneration, inflammatory diseases, multiple cancers, and kidney injury. The molecular regulation of necroptotic pathway has been intensively studied in recent years. Necroptosis can be triggered by multiple stimuli and this pathway is regulated through activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like (MLKL). A better understanding of the mechanism of regulation of necroptosis will further aid to the development of novel drugs for necroptosis-associated human diseases. In this review, we focus on new insights in the regulatory machinery of necroptosis. We further discuss the role of necroptosis in different pathologies, its potential as a therapeutic target and the current status of clinical development of drugs interfering in the necroptotic pathway.

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“…Cell death is an important driver of liver disease, while RIPKs were initially described as mediators of cell death and survival, emerging evidence indicates a necroptosis-independent role for the RIPKs in inflammation (9). Inhibition of RIPKs can decrease inflammatory response necroptotic cell death in vitro and in vivo (23). Oral RIPK1 inhibitor has been reported to be useful in inflammatory diseases, including psoriasis, inflammatory bowel disease, and rheumatoid arthritis (24,25).…”

Section: Discussionmentioning

confidence: 99%

The Role of RIPK1/3 in Adult Onset Still’s Disease Patients With Liver Damage: A Preliminary Study

et al. 2020

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ObjectiveThis study aimed to investigate the distributions of lymphocytes in adult onset Still’s disease (AOSD) with liver dysfunction, and further prospectively explore whether receptor interacting serine/threonine kinases (RIPKs) in lymphocytes play a role in the pathogenesis of AOSD especially liver involvement.MethodsSeventy-two AOSD patients and 19 cases of healthy controls (HCs) were retrospectively reviewed, the AOSD group was then divided into liver damage (LD) group and non-liver damage (NLD) group, and the distributions of lymphocytes in peripheral blood were analyzed. Another independent 24 AOSD patients and 20 HCs were recruited for prospective study of RIPKs; the RIPKs in peripheral blood lymphocytes were detected by flow cytometry. Liver biopsy specimens were obtained from two AOSD patients and underwent immunochemistry analysis with RIPK1 and RIPK3 antibody.ResultsIn the retrospective study, AOSD showed significantly abnormal lymphocytes distributions, and disease activity was positively correlated with percentage of CD3+ T cells. LD patients were younger in age and showed higher disease activity score than NLD patients; they had higher frequencies of CD3+ T cells, especially higher CD8+ T cells (all p<0.05). In the prospective study, RIPKs in lymphocytes were significantly higher in AOSD patients than that of HCs, and LD patients also showed higher RIPKs expression than NLD patients. In addition, RIPKs were positively correlated with erythrocyte sedimentation rate (ESR) and disease activity in AOSD patients and LD and NLD subgroups (all p<0.05). Further, RIPKs expression was confirmed in two AOSD patients’ liver. ROC curve analysis indicated that RIPKs in lymphocytes (%) could be potential biomarkers in the diagnosis of AOSD and liver damage.ConclusionsAbnormal lymphocytes distributions and RIPKs expression were detected in AOSD. Aberrant expression of RIPKs in lymphocytes might be involved in the pathogenesis of AOSD. RIPKs could be candidate markers for AOSD and liver damage.

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RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis

Cited by 40 publications

References 32 publications

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

The Role of RIPK1/3 in Adult Onset Still’s Disease Patients With Liver Damage: A Preliminary Study

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