Extracellular osmolarity regulates matrix homeostasis in the intervertebral disc and articular cartilage: evolving role of TonEBP.
Bottom Line: Thus, TonEBP-mediated regulation of the matrix composition allows disc cells and chondrocytes to modify the extracellular osmotic state itself.On the other hand, TonEBP in immune cells induces expression of TNF-α, ΙL-6 and MCP-1, pro-inflammatory molecules closely linked to matrix catabolism and pathogenesis of both disc degeneration and osteoarthritis, warranting investigations of this aspect of TonEBP function in skeletal cells.In summary, the TonEBP system, through its effects on extracellular matrix and osmoregulatory genes can be viewed primarily as a protective or homeostatic response to physiological loading.
Affiliation: Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA, United States.Show MeSH
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Mentions: Importantly, aside from regulating intracellular osmolarity, TonEBP is a key regulator of the content and, therefore, osmotic status of the extracellular matrix. Tsai et al. identified a consensus TonE element in the promoter of the aggrecan gene that functionally interacted with TonEBP (Fig. 1) (Tsai et al., 2006, 2007). Suppression of TonEBP activity by dominant negative protein or siRNA dramatically decreased aggrecan promoter activity. This was the first evidence in NP cells that TonEBP transcriptionally regulates matrix genes. Later investigations by our group showed that TonEBP also regulated the expression of β1,3-glucoronosyltransferase (GlcAT-I), an enzyme required for the synthesis of chondroitin sulfate chains of aggrecan (Hiyama et al., 2009). A follow-up study revealed that BMP-2 and TGF-β-mediated induction of GlcAT-I was also dependent on TonEBP activity (Hiyama et al., 2010). Based on these findings, it is clear that by controlling the expression and synthesis of aggrecan, TonEBP permits disc cells to autoregulate and adapt to their hyperosmotic state (Fig. 2).
Affiliation: Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA, United States.