Interleukin-6 signaling mediates cartilage degradation and pain in posttraumatic osteoarthritis in a sex-specific manner

Liao, Yihan; Ren, Yinshi; Luo, Xin; Mirando, Anthony J.; Long, Jason T; Leinroth, Abigail; Ji, Ru-Rong; Hilton, Matthew J.

doi:10.1126/scisignal.abn7082

Cited by 43 publications

(32 citation statements)

References 91 publications

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“…Transforming growth factor–α also decreases cartilage/bone degeneration and knee joint pain ( 47 ). Interleukin 6 (IL-6) mediates both cartilage degradation and pain associated with post-traumatic knee OA only in males ( 48 ). In contrast, protein kinase Cδ (PKCδ) null mice show reduced joint degeneration in knee OA but display greater pain ( 47 ).…”

Section: Preclinical Studies For Tmjoa and Pain From Tmjmentioning

confidence: 99%

The degeneration-pain relationship in the temporomandibular joint: Current understandings and rodent models

et al. 2023

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Temporomandibular disorders (TMD) represent a group of musculoskeletal conditions involving the temporomandibular joints (TMJ), the masticatory muscles and associated structures. Painful TMD are highly prevalent and conditions afflict 4% of US adults annually. TMD include heterogenous musculoskeletal pain conditions, such as myalgia, arthralgia, and myofascial pain. A subpopulations of TMD patients show structural changes in TMJ, including disc displacement or degenerative joint diseases (DJD). DJD is a slowly progressing, degenerative disease of the TMJ characterized by cartilage degradation and subchondral bone remodeling. Patients with DJD often develop pain (TMJ osteoarthritis; TMJ OA), but do not always have pain (TMJ osteoarthrosis). Therefore, pain symptoms are not always associated with altered TMJ structures, which suggests that a causal relationship between TMJ degeneration and pain is unclear. Multiple animal models have been developed for determining altered joint structure and pain phenotypes in response to various TMJ injuries. Rodent models of TMJOA and pain include injections to induce inflammation or cartilage destruction, sustained opening of the oral cavity, surgical resection of the articular disc, transgenic approaches to knockout or overexpress key genes, and an integrative approach with superimposed emotional stress or comorbidities. In rodents, TMJ pain and degeneration occur during partially overlapping time periods in these models, which suggests that common biological factors may mediate TMJ pain and degeneration over different time courses. While substances such as intra-articular pro-inflammatory cytokines commonly cause pain and joint degeneration, it remains unclear whether pain or nociceptive activities are causally associated with structural degeneration of TMJ and whether structural degeneration of TMJ is necessary for producing persistent pain. A thorough understanding of the determining factors of pain-structure relationships of TMJ during the onset, progression, and chronification by adopting novel approaches and models should improve the ability to simultaneously treat TMJ pain and TMJ degeneration.

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Section: Preclinical Studies For Tmjoa and Pain From Tmjmentioning

confidence: 99%

The degeneration-pain relationship in the temporomandibular joint: Current understandings and rodent models

et al. 2023

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“…IL6 and OSM are members of the IL6 family of cytokines and are produced by immune cells in response to tissue injury 70 . IL6 signaling is actively involved in regulating cartilage integrity and pain, implicating IL6 as a potential therapeutic target for murine post-traumatic knees 71 . Unfortunately, a recently conducted clinical trial of IL6 receptor antagonist, Tocilizumab, showed no significant pain relief in older subjects with hand OA when compared to placebo 72 .…”

Section: Resultsmentioning

confidence: 99%

Network-based cytokine inference implicates Oncostatin M as a driver for inflammation phenotype of knee osteoarthritis

Iijima

Zhang

Ambrosio

et al. 2023

Preprint

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Inflammatory cytokines released by the synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine-mediated pathological communication between the synovium and cartilage. Cartilage functional network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees. This finding was concomitant with accelerated cartilage degradation, as identified through meta-analysis of histological assessments. Next, cytokine inference with network propagation on the cartilage network uncovered IL6 family member, Oncostatin M (OSM), as a driver for osteoarthritis. Pharmacological manipulations confirmed that the aberrant matrix remodeling is attributed, at least partly, to downstream signals of OSM, but not IL6. These analyses implicate OSM as a promising therapeutic target to ameliorate osteoarthritis in aging through improved synovium-cartilage communication.

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“…Ketamine can relieve pain-induced depressive symptoms by enhancing the release of VEGFA and promoting neurogenesis in the hippocampus ( Deyama & Duman, 2020 ). As a multi-effect cytokine, IL-6 may promote the survival of hippocampal neurons to relieve pain ( Liao et al, 2022 ; Del Giudice & Gangestad, 2018 ). Cannabinoids can also enhance the expression of MAPK3 in HT22 hippocampal cells to protect nerve pain relief ( Olianas, Dedoni & Onali, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Regulatory mechanism of Scutellaria baicalensis Georgi on bone cancer pain based on network pharmacology and experimental verification

Wang

Guo

Cheng

et al. 2022

PeerJ

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Context Scutellaria baicalensis Georgi (SBG) may relieve bone cancer pain (BCP) by regulating cell proliferation, angiogenesis, and apoptosis. Objective The mechanism of SBG in the treatment of BCP remains to be further explored. Methods The active compounds and targets of SBG were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction databases. BCP-related targets were screened from NCBI and GeneCards databases. Additionally, Cytoscape software was applied to construct network diagrams, and OmicShare platform was used to enrich Gene Ontology (GO) and pathways. Finally, the verification of active compounds and core targets was performed based on quantitative real-time PCR (qRT-PCR). Results Interestingly, we identified baicalein and wogonin as the main active components of SBG. A total of 41 SBG targets, including VEGFA, IL6, MAPK3, JUN and TNF, were obtained in the treatment of BCP. In addition, pathways in cancer may be an essential way of SBG in the treatment of BCP. Experimental verification had shown that baicalein and wogonin were significantly related to BCP core targets. Conclusions The active components of SBG have been clarified, and the mechanism of the active components in treating BCP has been predicted and verified, which provides an experimental and theoretical basis for the in-depth elucidation of the pharmacodynamics material basis and mechanism of SBG.

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Interleukin-6 signaling mediates cartilage degradation and pain in posttraumatic osteoarthritis in a sex-specific manner

Cited by 43 publications

References 91 publications

The degeneration-pain relationship in the temporomandibular joint: Current understandings and rodent models

The degeneration-pain relationship in the temporomandibular joint: Current understandings and rodent models

Network-based cytokine inference implicates Oncostatin M as a driver for inflammation phenotype of knee osteoarthritis

Regulatory mechanism of Scutellaria baicalensis Georgi on bone cancer pain based on network pharmacology and experimental verification

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