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Background  Rheumatoid arthritis (RA) is a chronic, inflammatory and systemic autoimmune disease that leads to progressive cartilage destruction. Advances in the treatment of RA-related destruction of cartilage require profound insights into the molecular mechanisms involved in cartilage degradation. Until now, comprehensive data about the molecular RA-related dysfunction of chondrocytes have been limited. Hence, the objective of this study was to establish a standardized  in vitro  model to profile the key regulatory molecules of RA-related destruction of cartilage that are expressed by human chondrocytes.    Methods  Human chondrocytes were cultured three-dimensionally for 14 days in alginate beads and subsequently stimulated for 48 hours with supernatants from SV40 T-antigen immortalized human synovial fibroblasts (SF) derived from a normal donor (NDSF) and from a patient with RA (RASF), respectively. To identify RA-related factors released from SF, supernatants of RASF and NDSF were analyzed with antibody-based protein membrane arrays. Stimulated cartilage-like cultures were used for subsequent gene expression profiling with oligonucleotide microarrays. Affymetrix GeneChip Operating Software and Robust Multi-array Analysis (RMA) were used to identify differentially expressed genes. Expression of selected genes was verified by real-time RT-PCR.    Results  Antibody-based protein membrane arrays of synovial fibroblast supernatants identified RA-related soluble mediators (IL-6, CCL2, CXCL1–3, CXCL8) released from RASF. Genome-wide microarray analysis of RASF-stimulated chondrocytes disclosed a distinct expression profile related to cartilage destruction involving marker genes of inflammation ( adenosine A2A receptor ,  cyclooxygenase-2 ), the NF-κB signaling pathway ( toll-like receptor 2 ,  spermine synthase ,  receptor-interacting serine-threonine kinase 2 ), cytokines/chemokines and receptors ( CXCL1–3 ,  CXCL8 ,  CCL20 ,  CXCR4 ,  IL-1β ,  IL-6 ), cartilage degradation ( matrix metalloproteinase (MMP)-10 ,  MMP-12 ) and suppressed matrix synthesis ( cartilage oligomeric matrix protein ,  chondroitin sulfate proteoglycan 2 ).    Conclusion  Differential transcriptome profiling of stimulated human chondrocytes revealed a disturbed catabolic–anabolic homeostasis of chondrocyte function and disclosed relevant pharmacological target genes of cartilage destruction. This study provides comprehensive insight into molecular regulatory processes induced in human chondrocytes during RA-related destruction of cartilage. The established model may serve as a human  in vitro  disease model of RA-related destruction of cartilage and may help to elucidate the molecular effects of anti-rheumatic drugs on human chondrocyte gene expression.

Key regulatory molecules of cartilage destruction in rheumatoid arthritis: an in vitro study