Toll-like receptors in human chondrocytes and osteoarthritic cartilage.

Abstract

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.

• Authors: Tarvo Sillat, Gonçalo Barreto, Paul Clarijs, Antti Soininen, Mari Ainola, Jukka Pajarinen, Matti Korhonen, Yrjö T Konttinen, Regina Sakalyte, Mika Hukkanen, Pekka Ylinen, Dan C E Nordström
• Journal: Acta orthopaedica (Acta Orthop) Vol. 84 Issue 6 Pg. 585-92 (Dec 2013) ISSN: 1745-3682 [Electronic] Sweden
• PMID: 24237425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• TLR2 protein, human
• TLR9 protein, human
• Toll-Like Receptor 1
• Toll-Like Receptor 2
• Toll-Like Receptor 9
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha

Topics

• Cartilage, Articular (immunology)
• Cell Differentiation (immunology)
• Cells, Cultured
• Chondrocytes (immunology, pathology)
• Chondrogenesis (immunology)
• Female
• Gene Expression Regulation (immunology)
• Humans
• Male
• Mesenchymal Stem Cells (cytology, immunology)
• Osteoarthritis, Knee (immunology, pathology)
• RNA, Messenger (genetics)
• Severity of Illness Index
• Toll-Like Receptor 1 (biosynthesis, genetics)
• Toll-Like Receptor 2 (biosynthesis, genetics)
• Toll-Like Receptor 9 (biosynthesis, genetics)
• Toll-Like Receptors (biosynthesis, genetics)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics, immunology)