Exogenous fetuin-A protects against sepsis-induced myocardial injury by inhibiting oxidative stress and inflammation in mice.

Sepsis-induced myocardial injury is a consequence of septicemia and is one of the major causes of death in intensive care units. A serum glycoprotein called fetuin-A is secreted largely by the liver, tongue, placenta, and adipose tissue. Fetuin-A has a variety of biological and pharmacological properties. The anti-inflammatory and antioxidant glycoprotein fetuin-A has shown its efficacy in a number of inflammatory disorders including sepsis. However, its protective role against sepsis-induced myocardial injury remains elusive. The purpose of this work is to explore the role of fetuin-A in mouse models of myocardial injury brought on by cecal ligation and puncture (CLP). CLP significantly induced the myocardial injury assessed in terms of elevated myocardial markers (serum CK-MB, cTnI levels), inflammatory markers (IL-6, TNF-α) in the serum, and oxidative stress markers (increased MDA levels and decreased reduced glutathione) in heart tissue homogenate following 24 h of ligation and puncture. Further, hematoxylin and eosin (H&E) staining showed considerable histological alterations in the myocardial tissue of sepsis-developed mice. Interestingly, fetuin-A pretreatment (50 and 100 mg/kg) for 4 days before the CLP procedure significantly improved the myocardial injury and was evaluated in perspective of a reduction in the CK-MB, cTnI levels, IL-6, and TNF-α in sepsis-developed animals. Fetuin-A pretreatment significantly attenuated the oxidative stress and improved the myocardial morphology in a dose-dependent manner. The present study provides preliminary evidence that fetuin-A exerts protection against sepsis-induced cardiac dysfunction in vivo via suppression of inflammation and oxidative damage.

Fetuin-A and thyroxin binding globulin predict rituximab response in rheumatoid arthritis patients with insufficient response to anti-TNFα.

OBJECTIVES: Rheumatoid arthritis (RA) is a debilitating disease, but patient management and treatment have been revolutionized since the advent of bDMARDs. However, about one third of RA patients do not respond to specific bDMARD treatment without clear identified reasons. Different bDMARDs must be tried until the right drug is found. Here, we sought to identify a predictive protein signature to stratify patient responsiveness to rituximab (RTX) among patients with an insufficient response to a first anti-TNFα treatment. METHODS: Serum samples were collected at baseline before RTX initiation. A proteomics study comparing responders and nonresponders was conducted to identify and select potential predictive biomarkers whose concentration was measured by quantitative assays. Logistic regression was performed to determine the best biomarker combination to predict good or nonresponse to RTX (EULAR criteria after 6 months' treatment). RESULTS: Eleven biomarkers potentially discriminating between responders and nonresponders were selected following discovery proteomics. Quantitative immunoassays and univariate statistical analysis showed that fetuin-A and thyroxine binding globulin (TBG) presented a good capacity to discriminate between patient groups. A logistic regression analysis revealed that the combination of fetuin-A plus TBG could accurately predict a patient's responsiveness to RTX with an AUC of 0.86, sensitivity of 80%, and a specificity of 79%. CONCLUSION: In RA patients for whom a first anti-TNFα treatment has failed, the serum abundance of fetuin-A and TBG before initiating RTX treatment is an indicator for their response status at 6 months. ClinicalTrials.gov identifier: NCT01000441. Key Points • Proteomic analysis revealed 11 putative predictive biomarkers to discriminate rituximab responder vs. nonresponder RA patients. • Fetuin-A and TBG are significantly differentially expressed at baseline in rituximab responder vs. nonresponder RA patients. • Algorithm combining fetuin-A and TBG accurately predicts response to rituximab in RA patients with insufficient response to TNFi.

Recent Advances in the Management of Vascular Calcification in Patients with End-Stage Renal Disease.

BACKGROUND: Vascular calcification (VC) is common in patients with chronic kidney disease (CKD) including end-stage renal disease (ESRD). The pathogenesis of VC is complex, resulting in increased arterial stiffening, which is associated with cardiovascular mortality. In addition to traditional cardiovascular risk factors, CKD patients also have a number of non-traditional cardiovascular risk factors that may play an important role in the pathogenesis of VC. SUMMARY: Management of CKD-mineral bone disorder using conventional therapeutic approaches, which include restricting dietary phosphate, administering phosphate binders, and using active vitamin D and calcimimetics, may inhibit the progression of VC, but these approaches remain controversial because recommended biochemical targets are difficult to achieve. Current treatment strategies focus on correcting abnormal calcium, phosphate, parathyroid hormone, and vitamin D levels in ESRD patients. Novel therapies for addressing VC include magnesium and vitamin K supplementation, which are currently being investigated in randomized controlled trials. This review summarizes current treatment strategies and therapeutic targets for the management of VC in patients with ESRD. Key Messages: A better understanding of the potential therapeutic approaches to VC may lead to improved mortality rates among patients with CKD including those on dialysis. Fetuin-A inhibits VC by binding to the nanoparticles of calcium and phosphate, preventing mineral accretion. These particles are known as calciprotein particles and may provide an important pathway for mineral transport and clearance. This review article summarizes the current management of VC in patients with ESRD.

Role of vascular calcification inhibitors in preventing vascular dysfunction and mortality in hemodialysis patients.

Cardiovascular events make up the primary cause of death in hemodialysis patients, and the risk for cardiovascular mortality is significantly increased by vascular calcification, a condition observed frequently in this patient population. The mechanisms underlying the pathogenesis of vascular calcification are complex, and many factors facilitate or hinder the development of calcification. In this review, we first summarize the main factors contributing to the pathogenesis of vascular calcification in patients with end-stage renal disease. We then explore the role of calcification inhibitors in the calcification process, as well as their effect on vascular dysfunction and mortality in hemodialysis patients.

A single intraperitoneal injection of bovine fetuin-A attenuates bone resorption in a murine calvarial model of particle-induced osteolysis.

Particle-induced osteolysis, which by definition is an aseptic inflammatory reaction to implant-derived wear debris eventually leading to local bone destruction, remains the major reason for long-term failure of orthopedic endoprostheses. Fetuin-A, a 66kDa glycoprotein with diverse functions, is found to be enriched in bone. Besides being an important inhibitor of ectopic calcification, it has been described to influence the production of mediators of inflammation. Furthermore, a regulatory role in bone metabolism has been assigned. In the present study, the influence of a single dose of bovine fetuin-A, intraperitoneally injected in mice subjected to particle-induced osteolysis of the calvaria, was analyzed. Twenty-eight male C57BL/6 mice, twelve weeks of age, were randomly divided into four groups. Groups 2 and 4 were subjected to ultra-high molecular weight polyethylene (UHMWPE) particles placed on their calvariae while groups 1 and 3 were sham-operated. Furthermore, groups 3 and 4 received a single intraperitoneal injection of 20mg bovine fetuin-A while groups 1 and 2 were treated with physiologic saline. After 14days calvarial bone was qualitatively and quantitatively assessed using microcomputed tomography (µCT) and histomorphometrical approaches. Application of fetuin-A led to a reduction of particle-induced osteolysis in terms of visible osteolytic lesions and eroded bone surface. The reduction of bone thickness and bone volume, as elicited by UHMWPE, was alleviated by fetuin-A. In conclusion, fetuin-A was found to exert an anti-resorptive effect on particle-induced osteolysis in-vivo. Thus, fetuin-A could play a potentially osteoprotective role in the treatment of bone metabolic disorders.

Intraperitoneal administration of fetuin-A attenuates D-galactosamine/lipopolysaccharide-induced liver failure in mouse.

BACKGROUND: Fulminant hepatic failure (FHF) is a devastating syndrome, which sometimes results in death or liver transplantation, in which inflammation would aggravate the development of fetuin-A which would act as an anti-inflammatory factor and may be an available approach to attenuate FHF. AIMS: The purpose of this study was to investigate the effects of fetuin-A on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced liver failure in mice. METHODS: A mouse model of FHF induced by D-GalN/LPS was established and fetuin-A was injected intraperitoneally prior to D-GalN/LPS treatment. At different time points after D-GalN/LPS intervention, serum TNF-α and IL-6 levels were measured by ELISA. Fetuin-A mRNA and protein expression in liver tissues was assessed by RT-PCR, Western blotting and immunohistochemical staining. Besides, an observation of liver tissue injury, the apoptosis of hepatocytes, was analyzed by TUNEL assay. RESULTS: Expression of fetuin-A mRNA and protein in liver tissue were significantly and gradually decreased after D-GalN/LPS administration. A pre-intervention of exogenous fetuin-A significantly improved the liver function, decreased TNF-α and IL-6 expression in peripheral blood, and liver tissue inhibited hepatocyte apoptosis responded to D-GalN/LPS induction so as to decrease the mortality rates of FHF mouse. Meanwhile, fetuin-A was negatively correlated with the hepatic pathological score and TNF-α protein staining in FHF mouse. CONCLUSIONS: An intraperitoneal injection of fetuin-A attenuates D-GalN/LPS-induced FHF in mice. Fetuin-A might be a protective agent of liver damage partly through inhibiting liver inflammatory response and hepatocyte apoptosis.

Fetuin-A: a multifunctional protein.

Sixty-six years have elapsed since the discovery of fetuin in 1944, but its importance in mammalian physiology has only recently been appreciated. Fetuin, first isolated from fetal bovine serum and now most commonly known as either fetuin-A, alpha-2-HS-glycoprotein (recommended name by UniprotKB and PIR), or α2-Heremans-Schmid glycoprotein, functions as an important component of diverse normal and pathological processes, including vascular calcification and bone metabolism regulation, insulin resistance, protease activity control, keratinocytes migration, and breast tumor cell proliferative signaling. Fetuin-A has also been identified as a biomarker for neurodegenerative disease. Here, we summarize recent publications focusing on the structural and functional properties of fetuin-A. The emerging importance of fetuin-A for both diagnosis and therapeutics has come to the attention of the pharmaceutical industry. Therefore, we will discuss the status of patents based on fetuin-A.