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Tumor necrosis factor alpha downregulates bone morphogenetic protein expression and matrix macromolecule synthesis in articular cartilage
Arthritis Res Ther volume 6, Article number: 81 (2004)
Cartilage breakdown in arthritis is thought to result from disequilibrium of catabolic and anabolic mechanisms. Tumor necrosis factor (TNF) alpha is a potent stimulator of catabolic pathways, whereas its influence on anabolic pathways is currently unknown. Herein, we studied the effect of systemic overexpression of TNF on bone morphogenic protein (BMP) expression in articular cartilage and cartilage matrix synthesis.
Analyses were performed in human tumor necrosis factor transgenic (hTNFtg) mice, which suffer from chronic destructive arthritis, and wild-type mice. Expression of cartilage-derived morphogenetic protein (CDMP)-1, CDMP-2, and BMP-6 and BMP-7 in articular cartilage was assessed by immunohistochemistry. Cartilage samples from the knee joints were assessed for DNA content and [35S]sulfate incorporation assays to assess chondrocyte number and matrix synthesis, respectively.
Expression of all four BMP family members was significantly decreased in articular cartilage of hTNFtg mice. The numbers of stained cells were reduced by about 60% for CDMP-1, CDMP-2 and BMP-6 (P < 0.004) and by 44% for BMP-7 (P < 0.02). There was no difference in DNA content in the investigated cartilage samples, whereas isotope incorporation into newly synthesized matrix macromolecules was significantly decreased by an average of 61% in cartilage derived from hTNFtg mice compared with wild-type controls (P < 0.001).
Chronic overexpression of TNF leads to decreased expression of BMPs and reduced matrix macromolecule synthesis in the articular cartilage. These data suggest that TNF, aside from functioning as a catabolic mediator, potently inhibits anabolic mechanisms, which aim to restore the integrity of articular cartilage.
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Bobacz, K., Hayer, S., Kollias, G. et al. Tumor necrosis factor alpha downregulates bone morphogenetic protein expression and matrix macromolecule synthesis in articular cartilage. Arthritis Res Ther 6, 81 (2004). https://doi.org/10.1186/ar1417
- Tumor Necrosis Factor
- Articular Cartilage
- Morphogenetic Protein
- Bone Morphogenic Protein
- Matrix Synthesis