Therapeutic Benefit in Rheumatoid Cachexia Illustrated Using a Novel Primary Human Triple Cell Coculture Model

Abstract

Background. The loss of muscle mass in rheumatoid arthritis (RA), termed rheumatoid cachexia, is predicted to result from the complex interactions between different cell types involved in the maintenance of skeletal muscle mass, namely, myoblasts, fibroblasts, and macrophages. The complexity within the muscle is further highlighted by the incidence of nonresponsiveness to current RA treatment strategies. Method. This study aimed at determining differences in the cellular responses in a novel human primary cell triple coculture model exposed to serum collected from nonarthritic controls (NC), RA treatment naïve (RATN), and RA treatment-nonresponding (RATNR) patients. Bone morphogenetic protein-7 (BMP-7) was investigated as a treatment option. Results. Plasma analysis indicated that samples were indeed representative of healthy and RA patients—notably, the RATNR patients additionally exhibited dysregulated IL-6/IL-10 correlations. Coculture exposure to serum from RATNR patients demonstrated increased cellular growth ( $p<0.001$ ), while both hepatocyte growth factor ( $p<0.01$ ) and follistatin ( $p<0.001$ ) were reduced when compared to NC. Furthermore, decreased concentration of markers of extracellular matrix formation, transforming growth factor-β (TGF-β; $p<0.05$ ) and fibronectin ( $p<0.001$ ), but increased collagen IV ( $p<0.01$ ) was observed following RATNR serum exposure. Under healthy conditions, BMP-7 exhibited potentially beneficial results in reducing fibrosis-generating TGF-β ( $p<0.05$ ) and fibronectin ( $p<0.05$ ). BMP-7 further exhibited protective potential in the RA groups through reversing the aberrant tendencies observed especially in the RATNR serum-exposed group. Conclusion. Exposure of the triple coculture to RATN and RATNR serum resulted in dysregulated myoblast proliferation and growth, and ECM impairment, which was reversed by BMP-7 treatment.