Abstract:Background
Knee osteoarthritis (KOA) seriously affects the quality of life of KOA patients. This study aimed to investigate whether miR-107 could regulate KOA through pyroptosis to affect collagen protein secreted by chondrocytes through IL-1β.
Methods
The proliferation of chondrocytes was detected by CCK-8 assay. RT-qPCR analysis was used to identify miR-107 expression and transfection effects. The expression of Col II, IL-1β, IL-18, and MMP13 in … Show more
“…Inflammasome, in which caspase-1 is activated, was observed in many arthritic disorders involving the production of pro-inflammatory cytokines such as Il-1β [26]. Notably, the modulation of Cd36-Pparg pathways provides attractive options for the treatment of metabolic diseases [27], where caspase-1 is also a potential target molecule [16].…”
Section: Discussionmentioning
confidence: 99%
“…Taken together, the results presented here suggest caspase-1 to be a molecule with a major impact on the regulation of cartilage development and maintenance, at least regarding inflammatory and metabolic functions. Modulations of caspase-1 activity thus open further applications including clinical trials [16].…”
Section: Discussionmentioning
confidence: 99%
“…The link between lipid metabolism and caspase-1 is also supported by the fact that caspase-1-deficient mice develop obesity [15]. As such, caspase-1 is favored as a potential target molecule in clinical treatments [16].…”
Caspase-1, as the main pro-inflammatory cysteine protease, was investigated mostly with respect to inflammation-related processes. Interestingly, caspase-1 was identified as being involved in lipid metabolism, which is extremely important for the proper differentiation of chondrocytes. Based on a screening investigation, general caspase inhibition impacts the expression of Cd36 in chondrocytes, the fatty acid translocase with a significant impact on lipid metabolism. However, the engagement of individual caspases in the effect has not yet been identified. Therefore, the hypothesis that caspase-1 might be a candidate here appears challenging. The primary aim of this study thus was to find out whether the inhibition of caspase-1 activity would affect Cd36 expression in a chondrogenic micromass model. The expression of Pparg, a regulator Cd36, was examined as well. In the caspase-1 inhibited samples, both molecules were significantly downregulated. Notably, in the treated group, the formation of the chondrogenic nodules was apparently disrupted, and the subcellular deposition of lipids and polysaccharides showed an abnormal pattern. To further investigate this observation, the samples were subjected to an osteogenic PCR array containing selected markers related to cartilage/bone cell differentiation. Among affected molecules, Bmp7 and Gdf10 showed a significantly increased expression, while Itgam, Mmp9, Vdr, and Rankl decreased. Notably, Rankl is a key marker in bone remodeling/homeostasis and thus is a target in several treatment strategies, including a variety of fatty acids, and is balanced by its decoy receptor Opg (osteoprotegerin). To evaluate the effect of Cd36 downregulation on Rankl and Opg, Cd36 silencing was performed using micromass cultures. After Cd36 silencing, the expression of Rankl was downregulated and Opg upregulated, which was an inverse effect to caspase-1 inhibition (and Cd36 upregulation). These results demonstrate new functions of caspase-1 in chondrocyte differentiation and lipid metabolism-related pathways. The effect on the Rankl/Opg ratio, critical for bone maintenance and pathology, including osteoarthritis, is particularly important here as well.
“…Inflammasome, in which caspase-1 is activated, was observed in many arthritic disorders involving the production of pro-inflammatory cytokines such as Il-1β [26]. Notably, the modulation of Cd36-Pparg pathways provides attractive options for the treatment of metabolic diseases [27], where caspase-1 is also a potential target molecule [16].…”
Section: Discussionmentioning
confidence: 99%
“…Taken together, the results presented here suggest caspase-1 to be a molecule with a major impact on the regulation of cartilage development and maintenance, at least regarding inflammatory and metabolic functions. Modulations of caspase-1 activity thus open further applications including clinical trials [16].…”
Section: Discussionmentioning
confidence: 99%
“…The link between lipid metabolism and caspase-1 is also supported by the fact that caspase-1-deficient mice develop obesity [15]. As such, caspase-1 is favored as a potential target molecule in clinical treatments [16].…”
Caspase-1, as the main pro-inflammatory cysteine protease, was investigated mostly with respect to inflammation-related processes. Interestingly, caspase-1 was identified as being involved in lipid metabolism, which is extremely important for the proper differentiation of chondrocytes. Based on a screening investigation, general caspase inhibition impacts the expression of Cd36 in chondrocytes, the fatty acid translocase with a significant impact on lipid metabolism. However, the engagement of individual caspases in the effect has not yet been identified. Therefore, the hypothesis that caspase-1 might be a candidate here appears challenging. The primary aim of this study thus was to find out whether the inhibition of caspase-1 activity would affect Cd36 expression in a chondrogenic micromass model. The expression of Pparg, a regulator Cd36, was examined as well. In the caspase-1 inhibited samples, both molecules were significantly downregulated. Notably, in the treated group, the formation of the chondrogenic nodules was apparently disrupted, and the subcellular deposition of lipids and polysaccharides showed an abnormal pattern. To further investigate this observation, the samples were subjected to an osteogenic PCR array containing selected markers related to cartilage/bone cell differentiation. Among affected molecules, Bmp7 and Gdf10 showed a significantly increased expression, while Itgam, Mmp9, Vdr, and Rankl decreased. Notably, Rankl is a key marker in bone remodeling/homeostasis and thus is a target in several treatment strategies, including a variety of fatty acids, and is balanced by its decoy receptor Opg (osteoprotegerin). To evaluate the effect of Cd36 downregulation on Rankl and Opg, Cd36 silencing was performed using micromass cultures. After Cd36 silencing, the expression of Rankl was downregulated and Opg upregulated, which was an inverse effect to caspase-1 inhibition (and Cd36 upregulation). These results demonstrate new functions of caspase-1 in chondrocyte differentiation and lipid metabolism-related pathways. The effect on the Rankl/Opg ratio, critical for bone maintenance and pathology, including osteoarthritis, is particularly important here as well.
“… 75 In addition, some specific kinds of microRNA were proved to inhibit chondrocyte pyroptosis and delay progression of OA. 82–84 Figure 2 Hypotonicity causes inflammation and chondrocyte death. Presence of high concentration of proton and hypotonic microenvironment pathologically activates chloride channels on the chondrocyte membrane and enhances transmembrane Cl − current.…”
Section: Inflammatory Factors Apoptosis and Pyroptosis In Oamentioning
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.
“…Intriguingly, miR-107 up-modulation can intensify the proliferation and attenuate the pyroptosis of KOA cell model. 8 Some drugs are exerted its function in the treatment of KOA by modulating the expression of miRNAs, such as etoricoxib. It exhibits well therapeutic effect on KOA cases in the clinical by suppressing the level of serum miR-214 as well as inflammatory factors.…”
Purpose
This work was to identify the function and mechanism of miR‐219a‐5p in regulating knee osteoarthritis (KOA).
Methods
Rat fibroblast‐like synoviocytes (FLSs) were isolated to construct KOA cell model by lipopolysaccharide and adenosine triphosphate treatment. miR‐219a‐5p and FBXO3 expression in FLSs was modulated by transfection. Flow cytometry was executed to research FLSs apoptosis. Caspase‐1 and IL‐1β expression in FLSs was researched by immunofluorescence. The binding between miR‐219a‐5p and FBXO3 was identified by dual luciferase reporter gene assay. KOA rat model and miR‐219a‐5p up‐modulation KOA rat model were constructed. Step size of rats was analyzed. Knee joints of rats were experienced Safranin O‐fast green staining to evaluate the knee joint injury. FBXO3, pyroptosis‐associated proteins, and IL‐1β and IL‐18 expression in FLSs and articular cartilage tissues of rats were assessed by Western blot, qRT‐PCR and Enzyme‐linked immunosorbent assay.
Results
KOA cell model had higher apoptosis percentage, expression of pyroptosis‐associated proteins, and IL‐1β and IL‐18 level. miR‐219a‐5p up‐modulation decreased the above indicators, whereas miR‐219a‐5p down‐modulation increased the above indicators. FBXO3 expression was directly repressed by miR‐219a‐5p. Loss of FBXO3 suppressed the above indicators. FBXO3 counteracted the suppression of miR‐219a‐5p on the above indicators. miR‐219a‐5p agomir attenuated knee joint injury, increased step size of KOA rats, and reduced FBXO3, pyroptosis‐associated proteins and level of IL‐1β and IL‐18 in the articular cartilage tissues of KOA rats.
Conclusion
miR‐219a‐5p suppressed the pyroptosis in KOA by inactivating the NLRP3 signaling via targeting FBXO3, which might be a promising target for ameliorating KOA in the clinic.
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