ABSTRACT
The contribution of the NLRP3 inflammasome in osteoarthritis (OA) pathogenesis has been uncovered in recent years. Holomycin (HL) has recently been identified as a novel NLRP3 inflammasome inhibitor. Herein, we aimed to explore the benefits of HL for OA. A chondrocyte-macrophage co-culture system and the destabilization of the medial meniscus (DMM) mouse model were established to study the effect of HL on OA in vitro and in vivo. ECM degradation-related proteins (MMP-13, aggrecan, and Collagen II) were detected by Western blot (WB) and immunohistochemistry (IHC). The chondrocyte senescence was determined by cell cycle, p16 and p21 expressions, and SA-ß-Gal staining. The cartilage degeneration was evaluated by OARSI score and Safranin O and H&E staining. Inflammation and NLRP3 inflammasome activation were investigated via RT-PCR, ELISA, WB, and IHC. In vitro studies showed that IL-1ß stimulation caused a significant increase of MMP13, p16, p21, and ß-galactosidase expressions, a G1-phase arrest, and a down-regulation of aggrecan and Collagen II in chondrocytes, and the increased expressions of IL-6, CXCL-1, IL-1ß, NLRP3, and Caspase 1 p20 in both chondrocyte and macrophage. Meanwhile, HL administration could partly reverse these effects induced by IL-1ß. In DMM mouse models, intra-articular administration of HL alleviated cartilage degeneration and inflammation, as evidenced by the decrease of OARSI score and MMP13, p16, p21, Collagen II, IL-6, and CXCL-1 expressions and the restoration of chondrocyte number, proteoglycan, and MMP13 expression in cartilage tissues. This study identified HL as a promising agent for OA.
Subject(s)
Cartilage, Articular , Osteoarthritis , Mice , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Matrix Metalloproteinase 13/genetics , Matrix Metalloproteinase 13/metabolism , Aggrecans/metabolism , Inflammasomes/metabolism , Interleukin-6/metabolism , Osteoarthritis/pathology , Inflammation/pathology , Cartilage/metabolism , Chondrocytes/metabolism , Disease Models, Animal , Extracellular Matrix Proteins/metabolism , Collagen/metabolism , Cartilage, Articular/metabolismABSTRACT
BACKGROUND: Some studies have shown that the position of the tibial component in Oxford unicompartmental knee arthroplasty with a mobile bearing will affect the clinical outcome of patients. Hence, our study aimed to investigate the relationship between the overhang distance of the tibial component and the survival of the implant. METHODS: A retrospective analysis of patients who underwent unicompartmental knee arthroplasty at the same institution from 2014 to 2018 was presented. The study was divided into three groups: minor underhang group (underhang between -3 and 0 mm); minor overhang group (overhang 0-3 mm); and major overhang group (overhang ≥ 3 mm). Demographic and clinical profile characteristics of each group were compared, and survival curves of each group were also compared using Kaplan-Meier and modeled using multivariate Cox regression. RESULTS: A total of 351 knees were included in this study with a minimum follow up of three years and a mean follow up of 4.8 ± 1.5 years. The revision rates in each group were 3.6% (minor underhang group), 2.7% (minor overhang group), and 20.9% (major overhang group) (P < 0.001). From the three groups' cumulative survival rates, the major overhang group was significantly lower than the other two groups (log rank P < 0.001). Multivariate Cox regression showed an association between the major overhang group and implant survival rate (hazard ratio = 7.515, 95% confidence interval = 2.500-22.593, P < 0.001) CONCLUSION: The risk of revision will increase if the tibial component overhangs more than 3 mm medially. Moreover, the reasons for revision are generally bearing dislocation and aseptic loosening.
