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

Abstract

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.

Intra-articular adipose-derived mesenchymal stem cells from rheumatoid arthritis patients maintain the function of chondrogenic differentiation

“…Therefore we confirm that ADSCs are another cell subset in which chondrogenic properties are suppressed by TNF. The chondrogenesis of BMSCs is inhibited by TNF in NF-kB-dependent manner [27] and the chondrogenic capacity of FLS is inhibited by TNF through p38 mitogen activating kinase pathways [29]. In the rheumatoid synovium, MSCs have impaired chondrogenic potential due to the inflammatory environment (partially composed of TNF), and a negative relationship between synovial MSC chondrogenic capacity and magnitude of synovitis has been reported [30].…”

p38MAPK: stress responses from molecular mechanisms to therapeutics

“…Interestingly, up to a third of all TNF-induced genes in FLS are dependent on p38 MAPK signalling [17]. Not only does TNF contribute to destruction of bone and cartilage in RA [18-20], it also inhibits chondrocyte differentiation from FLS and neochondrogenesis [21]. p38 MAPK is implicated in the production of TNF, interleukin (IL)-1β and IL-6 amongst other inflammatory cytokines in the pathogenesis of RA (Table 2).…”

Effects of CD14 Macrophages and Proinflammatory Cytokines on Chondrogenesis in Osteoarthritic Synovium-Derived Stem Cells

“…33 Since SDSCs are used to facilitate cartilage tissue regeneration, it is critical to consider the effect of synovitis on chondrogenic differentiation of OA SDSCs since inflammatory cytokines have previously been shown to inhibit chondrogenesis. 27,28 CD14 is a glycoprotein expressed on the surface of myelomonocytic cells as a GPI-anchored receptor or secreted in a soluble form. 34 We observed a correlation between IL-1b and TNF-a levels of synovial fluid and CD14 levels in osteoarthritic SDSCs.…”

“…It has been reported that TNF-a inhibits the chondrogenic differentiation of synovial fibroblasts through p38 mitogen-activated protein kinase pathways; NFkB-dependent inhibition by IL-1b and TNF-a of the chondrogenic differentiation of human bone marrow (BM) MSCs has also been reported. 27,28 To date, however, the direct function of these factors with respect to repression of chondrogenic differentiation has not been clearly elucidated.…”