Introduction: Adiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis. Methods: Immunohistochemical analysis was performed to evaluate differential expression of adiponectin receptors (AdipoRs) in nonlesional and lesional areas of OA cartilage. Cartilage and chondrocytes from the knee joints of primary OA patients were cultured in the presence of adiponectin (0~30 μg/ml). The levels of total nitric oxide (NO), matrix metalloproteinase (MMP)-1, -3, and -13, and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in the conditioned media. The levels of inducible NO synthase (iNOS) and MMPs were determined with the quantitative real-time reverse transcription-polymerase chain reaction. The concentrations of collagenase-cleaved type II collagen neoepitope (C1-2C) were determined in the supernatant of adiponectin-stimulated OA cartilage explants. The effects of kinase and NOS inhibitors were evaluated in the adiponectin-stimulated chondrocytes. Results: The expression levels of both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of OA cartilage. The increased rate of AdipoR1-positive chondrocytes was twice that of AdipoR2-positive chondrocytes when compared between nonlesional and lesional areas. Adiponectin-stimulated OA chondrocytes showed increased total NO and MMP-1, -3, and -13 levels compared with nonstimulated cells. The TIMP-1 level was not affected. The C1-2C levels were increased by adiponectin in OA cartilage explant culture. AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) inhibitors (compound C and SP600125) significantly suppressed adiponectin-induced production of total NO and MMP-1, -3, and -13. Inducible NOS inhibitors enhanced the expression of the adiponectin-induced MMPs. Conclusions: Adiponectin causes matrix degradation in OA cartilage and increases MMPs and iNOS expression via the AMPK and JNK pathways in human OA chondrocytes. The catabolic effects of adiponectin may be counteracted by NO.

Introduction: Although IL-1β is believed to be crucial in the pathogenesis of osteoarthritis (OA), the IL-1β blockade brings no therapeutic benefit in human OA and results in OA aggravation in several animal models. We explored the role of a cytokine signaling 1 (SOCS1) suppressor as a regulatory modulator of IL-1β signaling in chondrocytes. Methods: Cartilage samples were obtained from patients with knee OA and those without OA who underwent surgery for femur-neck fracture. SOCS1 expression in cartilage was assessed with immunohistochemistry. IL-1β-induced SOCS1 expression in chondrocytes was analyzed with quantitative polymerase chain reaction and immunoblot. The effect of SOCS1 on IL-1β signaling pathways and the synthesis of matrix metalloproteinases (MMPs) and aggrecanase-1 was investigated in SOCS1-overexpressing or -knockdown chondrocytes. Results: SOCS1 expression was significantly increased in OA cartilage, especially in areas of severe damage (P < 0.01). IL-1β stimulated SOCS1 mRNA expression in a dose-dependent pattern (P < 0.01). The IL-1β-induced production of MMP-1, MMP-3, MMP-13, and ADAMTS-4 (aggrecanase-1, a disintegrin and metalloproteinase with thrombospondin motifs 4) was affected by SOCS1 overexpression or knockdown in both SW1353 cells and primary human articular chondrocytes (all P values < 0.05). The inhibitory effects of SOCS1 were mediated by blocking p38, c-Jun N-terminal kinase (JNK), and nuclear factor κB (NF-κB) activation, and by downregulating transforming growth factor-β-activated kinase 1 (TAK1) expression. Conclusions: Our results show that SOCS1 is induced by IL1-β in OA chondrocytes and suppresses the IL-1β-induced synthesis of matrix-degrading enzymes by inhibiting IL-1β signaling at multiple levels. It suggests that the IL-1β-inducible SOCS1 acts as a negative regulator of the IL-1β response in OA cartilage.

Background: In non-small cell lung cancer (NSCLC) patients, concomitant idiopathic pulmonary fibrosis (IPF) and emphysema (CPFE) are independently related to poor survival. CPFE is a condition with features of both pulmonary fibrosis and emphysema. Here, we evaluated the effect of CPFE and IPF alone on the outcomes of NSCLC patients.Patients and methods: We retrospectively evaluated 283 patients with CPFE or IPF who were diagnosed with NSCLC between November 2003 and February 2018 at two tertiary care hospitals in South Korea. Patients were classified into CPFE and IPF groups according to chest computed tomography findings.Results: One-hundred-and-seven patients (37.8%; mean age: 70.1 years; men 97.2%) had CPFE. Compared with IPF patients, CPFE patients had a heavier smoking history; lower diffusing capacity of carbon monoxide (78.0% vs 64.8%,p < 0.001), and lower forced expiratory volume in 1 s. Of all patients with NSCLC, 71.7% overall died during the follow-up period; 71.6% died in the CPFE group and 72.0% in the IPF group. Multivariate logistic regression analysis showed that CPFE (odds ratio [OR]: 2.26, 95% confidence interval [CI]: 1.09–4.69;P = 0.029) was significantly correlated with acute exacerbations (AEs). In a Cox proportional hazards analysis, stage > III NSCLC, higher Eastern Cooperative Oncology Group performance status, and higher gender–age–physiology index score was related to higher mortality. However, CPFE was not related to a higher mortality rate in univariate (hazard ratio [HR]: 1.00; 95% CI: 0.75–1.32,P = 0.972) or multivariate analysis (HR: 0.89; 95% CI: 0.66–1.21,P = 0.466).Conclusions: AE risk, but not all-cause mortality, was higher in patients with CPFE and NSCLC than in those with IPF and NSCLC. Physicians should be aware of the exaggerated risk of AE in patients with concomitant CPFE and NSCLC.