Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: A potential marker of erosive joint destruction

Abstract

Objective. The transforming growth factor ␤ superfamily member macrophage inhibitory cytokine 1 (MIC-1) is expressed upon macrophage activation, regulated by the p53 pathway, and linked to clinical events in atherosclerosis and cancer. Since rheumatoid arthritis (RA) shares similar etiopathologic mechanisms with the above diseases, we sought to determine the clinical utility of determining MIC-1 serum levels and MIC-1 genotype in the management of RA.Methods. Ninety-one RA patients were recruited. Serum was collected from 83 of these patients and synovial biopsy samples were collected from the remaining 8 patients. Of the 83 patients from whom serum was collected, 61 were treated on an outpatient basis (defined as having nonsevere disease), and 22 patients went on to undergo hemopoietic stem cell transplantation (HSCT) (defined as having severe disease).Results. Serum levels of MIC-1 were higher in RA patients and reflected disease severity independently of classic disease markers. MIC-1 was detected in rheumatoid synovial specimens, and allelic variation of MIC-1 was associated with earlier erosive disease and severe treatment-resistant chronic RA. Additionally, algorithms including serum and/or allelic variation in MIC-1 predicted response to HSCT, the presence of severe disease, and joint erosions.Conclusion. Determination of serum levels of MIC-1 and MIC-1 genotype may be clinically useful in the management of RA as well as in selection of patients for HSCT, since they predict disease course and response to therapy. The data indicate a potential role for MIC-1 in RA pathogenesis. These results warrant larger prospective studies to fully delineate and confirm a role for MIC-1 genotyping and serum estimation in patient selection for HSCT and in the management of RA.

Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet

“…However, its biological character and current knowledge about its effects in humans suggested that it might play an important role in the development and progression of inflammatory and atherosclerotic Table 4 Relationships of serum macrophage inhibitory cytokine-1 (MIC-1; pg/ml) with other anthropometric, hormonal, and biochemical parameters calculated in a combined population of all three study groups (A, nZ54) and in the combined group of obese patients (B and C, nZ31) both before and after very low calorie diet program (VLCD). processes and cancer (7,10,12). Recent data indicated a direct role for MIC-1 in energy homeostasis regulation in cachectic conditions making it a potentially interesting candidate molecule to modulate food intake and/or body adiposity (14).…”

“…Increased concentrations of MIC-1 were found in patients with chronic inflammatory states such as rheumatoid arthritis (7) and in many types of cancer (8)(9)(10). MIC-1 was also identified as a predictor of cardiovascular events in a cohort of previously healthy women (11,12) and as an early mediator of the injury response in kidney and lung (13).…”

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

“…Under hypoxic conditions in human umbilical vein endothelial cells in vitro, treatment with GDF-15 significantly enhances HIF1a-mediated expression of VEGF and also stabilizes the p53-MDM2 complex leading to ubiquitination and subsequent degradation of p53. 28 Besides cardiovascular tissue, elevated GDF-15 expression has been found in patients with rheumatoid arthritis, 29 congenital anemia 30,31 and metabolic disorders, such as obesity, diabetes mellitus or preeclampsia. 32,33 In cases of ineffective hematopoiesis, GDF-15 is likely involved in iron metabolism and erythrocyte differentiation.…”

Polymorphisms of the Genes EncodingCD40and Growth Differentiation Factor 15 and in the 9p21.3 Region in Patients with Rheumatoid Arthritis and Cardiovascular Disease

“…The D variant is not recognized by an antibody that is conformationdependent 29 , suggesting that the protein conformation has altered and that it may function differently. High serum levels of GDF15 and presence of the D allele were associated with an earlier onset of RA and were predictive of early erosive disease 30 .…”