Low dose of indomethacin and Hedgehog signaling inhibitor administration synergistically attenuates cartilage damage in osteoarthritis by controlling chondrocytes pyroptosis

Liu, Qingbai; Wu, Zaifeng; Hu, Dianlei; Zhang, Lin; Wang, Laijie; Liu, Gang

doi:10.1016/j.gene.2019.143959

Cited by 28 publications

(18 citation statements)

References 23 publications

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“…The chondrocyte inflammation model induced by LPS was effectively applied to reflect the degree of OA cartilage injury. These results are consistent with those reported previously 9,49–51 . However, the overexpression of TNF‐α was not observed with the treatment of OI in LPS‐induced ATDC5 cells.…”

Section: Discussionsupporting

confidence: 93%

4‐octyl Itaconate inhibits lipopolysaccharide (LPS)‐induced osteoarthritis via activating Nrf2 signalling pathway

Zhang

Bai

Wang

et al. 2022

J Cellular Molecular Medi

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Small molecule drug intervention for chondrocytes is a valuable method for the treatment of osteoarthritis (OA). The 4‐octyl itaconate (OI) is a cellular derivative of itaconate with sound cell permeability and transformation rate. We attempted to confirm the protective role of OI in chondrocytes and its regulatory mechanism. We used lipopolysaccharide (LPS) to induce chondrocyte inflammation injury. After the OI treatment, the secretion and mRNA expression of Il‐6, Il‐10, Mcp‐1 and Tnf‐α were detected by ELISA and qPCR. The protective effect of OI on articular cartilage was further verified in surgical destabilization of the medial meniscus model of OA. Cell death and apoptosis were evaluated based on CCK8, LDH, Typan blue staining, Annexin V and TUNEL analyses. The small interfering RNAs were used to knockout the Nrf2 gene of chondrocytes to verify the OI‐mediated Nrf2 signalling pathway. The results revealed that OI protects cells from LPS‐induced inflammatory injury and attenuates cell death and apoptosis induced by LPS. Similar protective effects were also observed on articular cartilage in mice. The OI activated Nrf2 signalling pathway and promoted the stable expression and translocation of Nrf2 into the nucleus. When the Nrf2 signalling pathway was blocked, the protective effect of OI was significantly counteracted in chondrocytes and a mouse arthritis model. Both itaconate and its derivative (i.e., OI) showed important medical effects in the treatment of OA.

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Section: Discussionsupporting

confidence: 93%

4‐octyl Itaconate inhibits lipopolysaccharide (LPS)‐induced osteoarthritis via activating Nrf2 signalling pathway

Zhang

Bai

Wang

et al. 2022

J Cellular Molecular Medi

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“… 36 , 85–87 And other researchers have designed some medication to restrict chondrocyte pyroptosis through regulating NLRP3 inflammatory in vitro, including icariin, indomethacin and loganin. 88–90 …”

Section: Inflammatory Factors Apoptosis and Pyroptosis In Oamentioning

confidence: 99%

Chloride Channel and Inflammation-Mediated Pathogenesis of Osteoarthritis

Lin¹,

Deng²,

Liu³

et al. 2022

JIR

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Articular cartilage allows the human body to buffer and absorb stress during normal exercise. It is mainly composed of cartilage cells and the extracellular matrix and is surrounded by the extracellular microenvironment formed by synovial fluid and various factors in it. Studies have shown that chondrocytes are the metabolic center of articular cartilage. Under physiological conditions, the extracellular matrix is in a dynamic balance of anabolism and catabolism, and various factors and physical and chemical conditions in the extracellular microenvironment are also in a steady state. This homeostasis depends on the normal function of proteins represented by various ion channels on chondrocytes. In mammalian chondrocyte species, ion channels are mainly divided into two categories: cation channels and anion channels. Anion channels such as chloride channels have become hot research topics in recent years. These channels play an extremely important role in various physiological processes. Recently, a growing body of evidence has shown that many pathological processes, abnormal concentration of mechanical stress and chloride channel dysfunction in articular cartilage lead to microenvironment disorders, matrix and bone metabolism imbalances, which cause partial aseptic inflammation. These pathological processes initiate extracellular matrix degradation, abnormal chondrocyte death, hyperplasia of inflammatory synovium and bony. Osteoarthritis (OA) is a common clinical disease in orthopedics. Its typical manifestations are joint inflammation and pain caused by articular cartilage degeneration, but its pathogenesis has not been fully elucidated. Focusing on the physiological functions and pathological changes of chloride channels and pathophysiology of aseptic inflammation furthers the understanding of OA pathogenesis and provides possible targets for subsequent medication development.

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“…In another study by Liu et al, the effect of combined use of HH signalling inhibitor GANT‐61 and a common clinical anti‐inflammatory drug indomethacin on cartilage injury and inflammation in experimental OA mice were observed. They reported that low dose of indomethacin and HH signalling inhibitor administration synergistically attenuates cartilage damage in OA by controlling chondrocytes pyroptosis …”

Section: Targeting Hedgehog In Oa Treatmentmentioning

confidence: 99%

Functional role of hedgehog pathway in osteoarthritis

Xiao

Deng

et al. 2019

Cell Biochemistry & Function

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The hedgehog signalling pathway is one of the key regulators of metazoan development, and it plays an important role in the regulation of a variety of developmental and physiological processes. But it is aberrantly activated in many human diseases, including osteoarthritis (OA). In this study, we have reviewed the association of hedgehog signalling pathway in the development and progression of OA and evaluated the efforts to target this pathway for the prevention of OA. Usually in OA, activation of hedgehog induces up-regulation of the expression of hypertrophic markers, including type X collagen, increases production of nitric oxide and prostaglandin E2, several matrix-degrading enzymes including matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motifs in human knee joint cartilage leading to cartilage degeneration, and thus contributes in OA. Targeting hedgehog signalling might be a viable strategy to prevent or treat OA. Chemical inhibitors of hedgehog signalling is promising, but they cause severe side effects. Knockdown of HH gene is not an option for OA treatment in humans because it is not possible to delete HH in larger animals. Efficient knockdown of HH achieved by local delivery of small interfering RNA in future studies utilizing large animal OA models might be a more efficient approach for the prevention of OA. However, it remains a major problem to develop one single scaffold due to the different physiological functions of cartilage and subchondral bones possess. More studies are necessary to identify selective inhibitors for efficiently targeting the hedgehog pathway in clinical conditions.

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Low dose of indomethacin and Hedgehog signaling inhibitor administration synergistically attenuates cartilage damage in osteoarthritis by controlling chondrocytes pyroptosis

Cited by 28 publications

References 23 publications

4‐octyl Itaconate inhibits lipopolysaccharide (LPS)‐induced osteoarthritis via activating Nrf2 signalling pathway

4‐octyl Itaconate inhibits lipopolysaccharide (LPS)‐induced osteoarthritis via activating Nrf2 signalling pathway

Chloride Channel and Inflammation-Mediated Pathogenesis of Osteoarthritis

Functional role of hedgehog pathway in osteoarthritis

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