P2X7 Receptor Induces Pyroptotic Inflammation and Cartilage Degradation in Osteoarthritis via NF‐<i>κ</i>B/NLRP3 Crosstalk

Li, Zihao; Huang, Ziyu; Zhang, He; Lu, Jinghan; You, Tian; Wei, Yuansong; Yang, Yue; Bai, Lan

doi:10.1155/2021/8868361

Cited by 79 publications

(70 citation statements)

References 38 publications

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“…CY-09 reduced bone loss in osteoarthritis modeling. However, the route of administration is achieved by intra-articular injection in the knee ( 62 ). At present, the research on OLT1177 in OP has not been reported.…”

Section: Potential Therapeutic Target Of Nlrp3 Inflammasome In Opmentioning

confidence: 99%

NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?

Jiang

Yang

et al. 2021

Front. Endocrinol.

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Osteoporosis is a systemic bone metabolism disease that often causes complications, such as fractures, and increases the risk of death. The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates the maturation and secretion of Caspase-1 dependent proinflammatory cytokines interleukin (IL)-1β and IL-18, mediates inflammation, and induces pyroptosis. The chronic inflammatory microenvironment induced by aging or estrogen deficiency activates the NLRP3 inflammasome, promotes inflammatory factor production, and enhances the inflammatory response. We summarize the related research and demonstrate that the NLRP3 inflammasome plays a vital role in the pathogenesis of osteoporosis by affecting the differentiation of osteoblasts and osteoclasts. IL-1β and IL-18 can accelerate osteoclast differentiation by expanding inflammatory response, and can also inhibit the expression of osteogenic related proteins or transcription factors. In vivo and in vitro experiments showed that the overexpression of NLRP3 protein was closely related to aggravated bone resorption and osteogenesis deficiency. In addition, abnormal activation of NLRP3 inflammasome can not only produce inflammation, but also lead to pyroptosis and dysfunction of osteoblasts by upregulating the expression of Caspase-1 and gasdermin D (GSDMD). In conclusion, NLRP3 inflammasome overall not only accelerates bone resorption, but also inhibits bone formation, thus increasing the risk of osteoporosis. Thus, this review highlights the recent studies on the function of NLRP3 inflammasome in osteoporosis, provides information on new strategies for managing osteoporosis, and investigates the ideal therapeutic target to treat osteoporosis.

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Section: Potential Therapeutic Target Of Nlrp3 Inflammasome In Opmentioning

confidence: 99%

NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?

Jiang

Yang

et al. 2021

Front. Endocrinol.

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“…It has been previously reported that the selective activator Bz-ATP increases P2X7 expression and induces the OA phenotype in primary chondrocytes (Li et al, 2021b). The results of animal experiments (Figures 1, 2) showed that changes in the expression level of P2X7 regulate autophagy and apoptosis in chondrocytes.…”

Section: Moderate and Excessive P2x7 Activation Has Opposing Effects On Mtor And Autophagy And Both Induce Er Stressmentioning

confidence: 69%

“…We previously reported (Zhang et al, 2019;Li et al, 2021b) that P2X7 expression was increased in the rat OA model. Furthermore, we observed that treadmill exercises effectively alleviated OA occurrence and development.…”

Section: Treadmill Exercise Increases P2x7 Expression Activates Early Stage Autophagy and Induces Er Stress-mediated Apoptosis During Oamentioning

confidence: 93%

“…Next, the ACLT group was further divided into five injection groups, A740003, rapamycin, rapamycin + Bz-ATP, MHY1485, and MHY1485 + A740003. Each knee joint was injected with 50 µL of solution twice a week, and the control groups were injected with the same volume of saline, as previously described (Li et al, 2021b). The injection concentrations of A740003, Bz-ATP, rapamycin, and MHY1485 were the same as those used in our in vitro experiments.…”

Section: Animals Treadmill Exercise and Knee-joint Injectionsmentioning

confidence: 99%

“…We previously reported that moderate-intensity exercise effectively alleviated cartilage loss and OA symptoms (Zhang et al, 2019). We also found that purinergic receptor P2X ligand gated ion channel 7 (P2X7) was involved in OA incidence and development (Li et al, 2021b); furthermore, its expression levels were closely related to biomechanical stress (Li et al, 2021a). However, it is still not known whether moderate-intensity exercises affect OA via the regulation of P2X7 expression.…”

Section: Introductionmentioning

confidence: 99%

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IRE1-mTOR-PERK Axis Coordinates Autophagy and ER Stress-Apoptosis Induced by P2X7-Mediated Ca2+ Influx in Osteoarthritis

Huang

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Moderate-intensity exercise can help delay the development of osteoarthritis (OA). Previous studies have shown that the purinergic receptor P2X ligand gated ion channel 7 (P2X7) is involved in OA development and progression. To investigate the effect of exercise on P2X7 activation and downstream signaling in OA, we used the anterior cruciate ligament transection (ACLT)-induced OA rat model and primary chondrocyte culture system. Our in vivo experiments confirmed that treadmill exercise increased P2X7 expression and that this effect was more pronounced at the later time points. Furthermore, P2X7 activation induced endoplasmic reticulum (ER) stress and increased the expression levels of ER stress markers, such as 78 kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1), and activating transcription factor 6 (ATF6). At the early time points, IRE1 and PERK were activated, and mTOR was inhibited. At the later time points, mTOR was activated, mediating PERK to promote ER stress-apoptosis, whereas IRE1 and autophagy were inhibited. To confirm our observations in vitro, we treated primary chondrocytes with the P2X7 agonist benzoylbenzoyl-ATP (Bz-ATP). Our results confirmed that P2X7-mediated Ca2+ influx activated IRE1-mediated autophagic flux and induced PERK-mediated ER stress-apoptosis. To further investigate the role of P2X7 in OA, we injected mTOR antagonist rapamycin or P2X7 antagonist A740003 into the knee joints of ACLT rats. Our results demonstrated that mTOR inhibition induced autophagy, decreased apoptosis, and reduced cartilage loss. However, injection of mTOR agonist MHY1485 or Bz-ATP had the opposite effect. In summary, our results indicated that during the early stages of moderate-intensity exercise, P2X7 was activated and autophagic flux was increased, delaying OA development. At the later stages, P2X7 became over-activated, and the number of apoptotic cells increased, promoting OA development. We propose that the IRE1-mTOR-PERK signaling axis was involved in the regulation of autophagy inhibition and the induction of apoptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA, suggesting that the intensity and duration of exercise play a critical role. We also demonstrated that on a molecular level, P2X7 and its downstream pathways could be potential therapeutic targets for OA.

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Pannexin 3 activates P2X7 receptor to mediate inflammation and cartilage matrix degradation in temporomandibular joint osteoarthritis

Xiao

Zhang

et al. 2023

Cell Biology International

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Pannexin 3 (Panx3) is involved in regulation of the proliferation and differentiation in chondrocytes and pathological process in osteoarthritis, but its role and potential mechanism in temporomandibular joint osteoarthritis (TMJOA) are still unclear, which are thus explored in our research. We established TMJOA animal model and cell model. In vivo, after silencing Panx3, the pathological changes of condylar cartilage tissue were analyzed by tissue staining, while expressions of Panx3, P2X7 receptor (P2X7R), NLRP3, and cartilage matrix-related genes were measured by immunohistochemistry (for animal model) or immunofluorescence (for cell model), quantitative reverse-transcription polymerase chain reaction (qRT-PCR) or western blot. In addition, the activation of inflammation-related pathways was detected by qRT-PCR or western blot, and intracellular adenosine triphosphate (ATP) level was tested by ATP kit. The role of Panx3 in TMJOA was proved by loss-and gain-offunction assays. P2X7R antagonist was employed to verify the relationship between Panx3 and P2X7R. Panx3 silencing alleviated the damage of condyle cartilage tissue in TMJOA rats, and reduced expressions of Panx3, P2X7R, cartilage matrix degradation related-enzymes, and NLRP3 in condyle cartilage tissue. In TMJOA cell model, the expressions of Panx3, P2X7R, cartilage matrix degradation relatedenzymes were increased, and inflammation-related pathways were activated, meanwhile interleukin-1β treatment promoted the release of intracellular ATP to the extracellular space. The above-mentioned response was enhanced by Panx3 overexpression and reversed by Panx3 silencing. P2X7R antagonist reversed the regulation of Panx3 overexpression. In conclusion, Panx3 may activate P2X7R by releasing ATP to mediate inflammation and cartilage matrix degradation in TMJOA.

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P2X7 Receptor Induces Pyroptotic Inflammation and Cartilage Degradation in Osteoarthritis via NF‐κB/NLRP3 Crosstalk

Cited by 79 publications

References 38 publications

NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?

NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?

IRE1-mTOR-PERK Axis Coordinates Autophagy and ER Stress-Apoptosis Induced by P2X7-Mediated Ca2+ Influx in Osteoarthritis

Pannexin 3 activates P2X7 receptor to mediate inflammation and cartilage matrix degradation in temporomandibular joint osteoarthritis

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