AB0060 Cross-Talk between the Adipogenic and the Chondrogenic Programs Elicited by A Glycosaminoglycan Mixture

Background Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into chondrocytes, osteoblasts and adipocytes in a competitively balanced manner. MSCs play a role in the homeostasis of adipose tissue and joint tissues and provide potential for intervention in both obesity and degenerative joint disease (osteoarthritis). Nutritional and pharmacological factors influencing the differentiation fate of MSCs are of interest. Objectives To test the impact of a mixture of glycosaminoglycans (GAGs) used in osteoarthritis management (Oralvisc™, Bioiberica S.A., Palafolls, Spain) on the differentiation fate of multipotent cells. Methods Primary mouse embryo fibroblasts (MEFs), which like MSCs have the potential to differentiate into different mesenchymal cell types, were used as a model system. Post-confluent monolayer MEF cultures maintained in growth medium (non-stimulated conditions) or hormonally stimulated to differentiate into adipocytes were chronically exposed to a GAG mixture, its individual components or vehicle. In some experiments, bone morphogenetic protein 2 (BMP2), a known inducer of chondrogenic differentiation of MEFs, was used for comparison. The impact on adipocyte appearance, gene expression of chondrogenic markers, and gene expression of metabolic and adipokine genes was studied. Results Exposure to the GAG mixture, but not its individual components, suppressed spontaneous adipogenesis of MEFs, as it prevented the appearance of lipid-filled cells and the expression of adipogenic marker genes (Pparg, Cebpa, Fasn) in the non-stimulated cultures. The GAG mixture and BMP2 elicited strikingly similar time-course changes in the expression of both chondrogenic-related genes, with an early transient induction of Pref-1 followed by a marked induction of aggrecan, and adipogenic-related genes, with a generalized down-regulation coincident with aggrecan gene induction. HA did not reproduce these effects. Exposure to the GAG mixture did not prevent hormonally induced adipogenesis, but changed gene expression of MEFs in the adipose state, triggering a down-regulation of lipogenic genes (Cebpa, Fasn), an up-regulation of oxidative metabolism-related genes (Ppargc1a, Mtco2), and a down-regulation of genes coding for two insulin resistance-related adipokines (resistin and retinol binding protein 4); again, these effects were not elicited by individual components of the mixture alone. Conclusions A GAG mixture can tip the adipogenic/chondrogenic fate balance of multipotent mesenchymal cells towards chondrogenesis and, under adipogenic conditions, favor the differentiation of adipocytes with a more favorable metabolic and secretory gene expression profile. Synergism between individual GAGs in the mixture is involved in these effects. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5516