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Differential Toll-like receptor-dependent collagenase expression in chondrocytes
Arthritis Research & Therapy volume 9, Article number: P39 (2007)
To characterise the catabolic response of osteoarthritic (OA) chondrocytes to ligands that activate the complete repertoire of Toll-like receptors (TLRs).
The induction of MMP-1 and MMP-13, the collagenases, by ligands that activate the complete repertoire of TLRs was assessed in OA chondrocytes by quantitative RT-PCR. TLR ligand signalling pathway activation and their role in collagenase induction was analysed by western blotting and selective pathway inhibitors and siRNA. TLR ligand expression was compared in total RNA from femoral head cartilage of normal (neck of femur fracture) and OA patients undergoing joint replacement surgery.
All the ligands upregulated MMP-1 and MMP-13, although to differing degrees, indicating differential regulation of the collagenases and indicating that chondrocytes express most TLRs. MALP-2 (TLR6/2 ligand) and poly(IC) (a dsRNA mimicking TLR3 ligand) most robustly upregulated MMP-1 and MMP-13, respectively. Using siRNA the activation of MMP-13 by TLR3 and TLR6/2 ligands were confirmed to be via the adaptor Trif and MyD88. The induction of both MMP-1 and MMP-13 by TLR1/2, TLR3 and TLR6/2 ligands were dependent upon the NF-κB pathway. Interestingly, MMP-1 and MMP-13 induction by the three TLR ligands were differentially inhibited by various MAPK inhibitors, with MMP-13 induction sensitive to ERK pathway inhibition. In a cartilage resorption assay, TLR1/2 and TLR6/2 ligands, but not TLR3 ligand, led to significant collagen release. The expression profile of TLRs in neck of femur and OA cartilage revealed a highly significant (P < 0.001) downregulation of TLR2 and upregulation of TLR3.
Our gene expression profile reveals that chondrocytes express a large repertoire of TLRs, which upon activation leads to collagenase gene activation. The TLR1/2 and TLR6/2 ligands, which resulted in cartilage collagen resorption, require TLR2, whose expression is significantly repressed in end-stage OA. These data suggest modulation of TLR-mediated signalling, particularly via TLR2, as a potential therapeutic strategy for OA prevention.
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Zhang, Q., Hui, W., Davidson, R. et al. Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Arthritis Res Ther 9 (Suppl 3), P39 (2007). https://doi.org/10.1186/ar2265
- Cartilage Collagen
- Femoral Head Cartilage
- Complete Repertoire
- Resorption Assay