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Background Osteoarthritis (OA) is a common degenerative disease, and tumor necrosis factor (TNF-α) is known to play a critical role in OA. Cortistatin (CST) is a neuropeptide discovered over 20 years ago, which plays a vital role in inflammatory reactions. However, it is unknown whether CST is involved in cartilage degeneration and OA development. Methods The interaction between CST and TNF-α receptors was investigated through Coimmunoprecipitation and Biotin-based solid-phase binding assay. Western blot, Real-time PCR, ELISA, immunofluorescence staining, nitrite production assay and DMMB assay of GAG were performed for the primary chondrocyte experiments. Surgically induced and spontaneous OA models were established and western blot, flow cytometry, Real-time PCR, ELISA, immunohistochemistry and fluorescence in vivo imaging were performed for in vivo experiments. Findings CST competitively bound to TNFR1 as well as TNFR2. CST suppressed proinflammatory function of TNF-α. Both spontaneous and surgically induced OA models indicated that deficiency of CST led to an accelerated OA-like phenotype, while exogenous CST attenuated OA development in vivo. Additionally, TNFR1- and TNFR2-knockout mice were used for analysis and indicated that TNFRs might be involved in the protective role of CST in OA. CST inhibited activation of the NF-κB signaling pathway in OA. Interpretation This study provides new insight into the pathogenesis and therapeutic strategy of cartilage degenerative diseases, including OA. Fund The National Natural Science Foundation of China , the Natural Science Foundation of Shandong Province , Key Research and Development Projects of Shandong Province and the Cross-disciplinary Fund of Shandong University .

Background Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of β-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD. Methods Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples. Development of GD in PGRN-deficient mice was characterized, and the therapeutic effect of rPGRN on GD analyzed. Findings Serum PGRN levels were significantly lower in GD patients (96.65 ± 53.45 ng/ml) than those in healthy controls of the general population (164.99 ± 43.16 ng/ml, p, Highlights • The serum levels of PGRN is significantly lower in Gaucher's disease patients. • 4 GRN gene SNPs exhibit significantly higher frequencies in Gaucher's disease patients. • Both OVA-challenged and aged PGRN deficient mice develop Gaucher-like disease. • PGRN deficiency causes GCase aggregation and absence in lysosomes. • rPGRN protein is therapeutic against Gaucher's disease. The present study revealed 1) PGRN was isolated as an unexpected molecule associated with GD in addition to GCase; 2) deficiency or insufficiency of PGRN contributes to Gaucher's disease in mice and humans; 3) PGRN is required for the lysosomal localization of GCase; 4) measuring serum levels of PGRN and detecting variants in GRN may be employed as biochemical and genetic diagnostic approaches for GD; 5) novel therapeutic utilities for treating GD may implement PGRN in addition to recombinant GCase; and 6) this study also presents an unique mouse model that mimics the cardinal signs of human GD, including the typical tubular-like lysosomes in macrophages always seen in human GD patients, but not observed in any GD animal models previously reported.