Atsttrin regulates osteoblastogenesis and osteoclastogenesis through the TNFR pathway.

Osteoporosis is a systemic metabolic bone disorder for which inflammatory cytokines play an important role. To develop new osteoporosis treatments, strategies for improving the microenvironment for osteoblast and osteoclast balance are needed. Tumor necrosis factor-α (TNF-α) plays an important role in the initiation and development of osteoporosis. Atsttrin is an engineered protein derived from the growth factor, progranulin (PGRN). The present study investigates whether Atsttrin affects osteoclast formation and osteoblast formation. Here we show Atsttrin inhibits TNF-α-induced osteoclastogenesis and inflammation. Further mechanistic investigation indicates Atsttrin inhibits TNF-α-induced osteoclastogenesis through the TNFR1 signaling pathway. Moreover, Atsttrin rescues TNF-α-mediated inhibition of osteoblastogenesis via the TNFR1 pathway. Importantly, the present study indicates that while Atsttrin cannot directly induce osteoblastogenesis, it can significantly enhance osteoblastogenesis through TNFR2-Akt-Erk1/2 signaling. These results suggest that Atsttrin treatment could potentially be a strategy for maintaining proper bone homeostasis by regulating the osteoclast/osteoblast balance. Additionally, these results provide new insights for other bone metabolism-related diseases.

Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling.

Background: Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects. Objective: This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein. Methods: We exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin. Results: Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells. Conclusion: These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

The causal relationship between metabolic factors, drinking, smoking and intrahepatic cholangiocarcinoma: a Mendelian randomization study.

Background: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. While multiple risk factors for iCCA have been established, metabolic diseases (obesity, diabetes, NAFLD, dyslipidemia, and hypertension) and other risk factors, including smoking and drinking, are still controversial due to their potential confounders. Here, Mendelian randomization (MR) analysis was performed to identify the causal relationship between them. Method: In this study, we obtained GWAS data related to exposures from corresponding large genome-wide association studies. Summary-level statistical data for iCCA were obtained from the UK Biobank (UKB). We performed a univariable MR analysis to identify whether genetic evidence of exposure was significantly associated with iCCA risk. A multivariable MR analysis was conducted to estimate the independent effects of exposures on iCCA. Results: Univariable and multivariable MR analysis based on the large GWAS data indicated that there is little evidence to support the genetic role of metabolic factors, smoking, drinking, and NAFLD in iCCA development (P >0.05). In contrast to most current studies, their impact on iCCA development, if any, might be smaller than we thought. The previous positive results might be due to the comorbidities between diseases and potentially unavoidable confounding factors. Conclusion: In this MR study, we found no strong evidence to support causal associations between metabolic factors, NAFLD, smoking, drinking, and iCCA risk.