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Tumor necrosis factor-alpha inhibits chondrogenic differentiation of synovial fibroblasts through p38 mitogen activating protein kinase pathways.

150 150 NZ Stem Cell Treatment Centre

Mod Rheumatol. 2008;18(4):366-78
Authors: Okuma-Yoshioka C, Seto H, Kadono Y, Hikita A, Oshima Y, Kurosawa H, Nakamura K, Tanaka S

We previously reported that synovial fibroblast-like cells (SFs) can be differentiated into chondrocytes through activin receptor-like kinase (ALK) 3 activation. The aim of this study was to clarify the effect and signaling pathways of tumor necrosis factor (TNF)-alpha on the chondrogenic differentiation of SFs. Primary SFs from patients with rheumatoid arthritis (RA) were treated with recombinant human bone morphogenetic protein-2 or transduced with a constitutively active mutant of the ALK3 gene (ALK3CA) with or without TNF-alpha, and then cultured in pellets. Expression of chondrocyte-specific genes was analyzed by real-time polymerase chain reaction or by histological analysis. Inhibitors of mitogen-activating protein kinase (MAPK) pathways or adenovirus vectors carrying a dominant-negative mutant of the IkappaB kinase 2 gene (AxIKK2DN) were used to analyze the signaling pathways of TNF-alpha. Expression of chondrocyte-specific genes was induced in SFs either by rhBMP-2 treatment or by ALK3CA transduction, which was strongly suppressed by TNF-alpha treatment. TNF-alpha markedly increased the p38 MAPK pathways in SFs, and inhibition of p38 MAPK activation partially restored the inhibitory effect of TNF-alpha on the chondrogenic differentiation of SFs. Combination therapy BMP-2 and anti-TNF-alpha agents especially targeting p38 MAPK might be a good approach to stimulating neochondrogenesis in the damaged joints in RA.

PMID: 18437285 [PubMed – indexed for MEDLINE]