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Published on: January 7, 2019
Toll-like receptors in human chondrocytes and osteoarthritic cartilage
Tarvo Sillat1, Gonçalo Barreto, Paul Clarijs
1Institute of Clinical Medicine, Department of Medicine, Helsinki University Central Hospital;
Background And Purpose:
Degenerating cartilage releases potential danger signals that react with Toll-like receptor (TLR) type danger receptors. We investigated the presence and regulation of TLR1, TLR2, and TLR9 in human chondrocytes.
Methods:
We studied TLR1, TLR2, TLR4, and TLR9 mRNA (qRT-PCR) and receptor proteins (by immunostaining) in primary mature healthy chondrocytes, developing chondrocytes, and degenerated chondrocytes in osteoarthritis (OA) tissue sections of different OARSI grades. Effects of a danger signal and of a pro-inflammatory cytokine on TLRs were also studied.
Results:
In primary 2D-chondrocytes, TLR1 and TLR2 were strongly expressed. Stimulation of 2D and 3D chondrocytes with a TLR1/2-specific danger signal increased expression of TLR1 mRNA 1.3- to 1.8-fold, TLR2 mRNA 2.6- to 2.8-fold, and TNF-α mRNA 4.5- to 9-fold. On the other hand, TNF-α increased TLR1 mRNA] expression 16-fold, TLR2 mRNA expression 143- to 201-fold, and TNF-α mRNA expression 131- to 265-fold. TLR4 and TLR9 mRNA expression was not upregulated. There was a correlation between worsening of OA and increased TLR immunostaining in the superficial and middle cartilage zones, while chondrocytes assumed a CD166(×) progenitor phenotype. Correspondingly, TLR expression was high soon after differentiation of mesenchymal stem cells to chondrocytes. With maturation, it declined (TLR2, TLR9).
Interpretation:
Mature chondrocytes express TLR1 and TLR2 and may react to cartilage matrix/chondrocyte-derived danger signals or degradation products. This leads to synthesis of pro-inflammatory cytokines, which stimulate further TLR and cytokine expression, establishing a vicious circle. This suggests that OA can act as an autoinflammatory disease and links the old mechanical wear-and-tear concept with modern biochemical views of OA. These findings suggest that the chondrocyte itself is the earliest and most important inflammatory cell in OA.
Insights
Mature chondrocytes express Toll-like receptors (TLR1 and TLR2) and can initiate inflammation in osteoarthritis (OA). This creates a self-perpetuating cycle, suggesting chondrocytes are key inflammatory cells in OA.
Area of Science:
- Immunology
- Biochemistry
- Cell Biology
Background:
- Degenerating cartilage releases danger signals that interact with Toll-like receptors (TLRs).
- The role of TLRs in human chondrocytes, particularly in osteoarthritis (OA), requires further investigation.
Purpose of the Study:
- To investigate the presence and regulation of Toll-like receptor 1 (TLR1), Toll-like receptor 2 (TLR2), and Toll-like receptor 9 (TLR9) in human chondrocytes.
- To understand the role of these receptors in the context of osteoarthritis.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) and immunostaining were used to analyze TLR1, TLR2, TLR4, and TLR9 mRNA and protein expression.
- Primary mature healthy chondrocytes, developing chondrocytes, and degenerated chondrocytes from OA tissues (graded by OARSI) were studied.
- The effects of danger signals and pro-inflammatory cytokines on TLR expression were examined.
Main Results:
- Mature chondrocytes exhibited strong expression of TLR1 and TLR2.
- Stimulation with a TLR1/2-specific danger signal increased TLR1, TLR2, and TNF-α mRNA expression.
- Tumor necrosis factor-alpha (TNF-α) significantly upregulated TLR1, TLR2, and TNF-α mRNA expression, indicating a positive feedback loop.
- TLR4 and TLR9 mRNA expression did not increase.
- Increased TLR immunostaining correlated with OA severity, and chondrocytes adopted a progenitor phenotype.
Conclusions:
- Mature chondrocytes express TLR1 and TLR2, responding to cartilage-derived danger signals.
- This response triggers pro-inflammatory cytokine synthesis, leading to a self-amplifying inflammatory cycle.
- These findings position chondrocytes as critical early inflammatory cells in OA, linking mechanical and biochemical aspects of the disease.
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