Abstract
Tonicity-responsive enhancer-binding protein (TonEBP; nuclear factor of activated T cells 5) is a transcription factor that responds to changes in osmolality. However, recent studies have shown that it also modulates immune responses under inflammatory conditions independently of hyperosmolality. Fibronectin fragments (FN-fs), which are abundant in the synovial fluid of patients with osteoarthritis (OA), induce expression of matrix metalloproteinases (MMPs) via the toll-like receptor-2 (TLR-2) signaling pathway. In this study we examined whether TonEBP is involved in 29-kDa FN-f-induced expression of MMPs. The expression of TonEBP was significantly higher in human osteoarthritis compared with normal cartilage samples. 29-kDa FN-f affected the expression of MMPs 1, 3, and 13 via TonEBP, and expression and nuclear accumulation of TonEBP were induced by activation of the phospholipase C/NF-κB/MAPK signaling pathway and, in particular, modulated by TLR-2. In addition, 29-kDa FN-f induced the expression of osmoregulatory genes, including Tau-T, SMIT, and AR, as well as voltage-dependent calcium channels via the TonEBP/TLR-2 signaling pathway. These results show that 29-kDa FN-f upregulates MMPs in chondrocytes via the TLR-2/TonEBP signaling pathway.
Highlights
Tonicity-responsive enhancer-binding protein (TonEBP; nuclear factor of activated T cells 5) is a transcription factor that responds to changes in osmolality
The TonEBP mRNA level increased in control chondrocytes in a time-dependent manner; this increase was not accompanied by an increase in protein expression
Treatment with 29-kDa Fibronectin fragments (FN-fs) increased the nuclear localization of TonEBP to a degree comparable with that observed in a positive control induced by hyperosmolarity (NaCl, 110 mM) (Fig. 1D)
Summary
Tonicity-responsive enhancer-binding protein (TonEBP; nuclear factor of activated T cells 5) is a transcription factor that responds to changes in osmolality. Another study showed that β1,3-glucuronosyltransferase (GlcATI), an enzyme required for the synthesis of chondroitin sulfate chains, was positively regulated by TonEBP in response to ionophores in intervertebral disc cells[9] These findings indicate that TonEBP upregulates ECM in response to changes in osmolarity in the intervertebral disc cartilage, which acts as a shock absorber of the spine. In NP chondrocytes, RNA sequencing showed that 8.5% of TNF-α transcriptional responses were TonEBP dependent, and these genes were enriched in pathways related to inflammatory responses and inhibition of matrix metalloproteinases (MMPs)[12]. These results suggest that tonicity-independent stimulation of TonEBP plays a pleiotropic role in inflammation, angiogenesis, cell proliferation, and cartilage degeneration. The influence of TonEBP on OA articular cartilage has not been reported
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