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Extracellular osmolarity regulates matrix homeostasis in the intervertebral disc and articular cartilage: evolving role of TonEBP.

Johnson ZI, Shapiro IM, Risbud MV - Matrix Biol. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA, United States.

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Schematic representation of the osmotic response in healthy (left panel) and degenerative (right panel) disc or articular cartilage tissues. In healthy tissue, hyperosmolarity results from high negative charge of proteoglycans resulting in influx of NaCl. Hyperosmolarity results in robust increase in TonEBP mRNA, protein, and nuclear shuttling. TonEBP binds to TonE sites in target promoters to drive expression of osmotic response genes (blue) (AR, BGT1, SMIT, TauT), protecting against cellular damage during hypertonic stress. Similarly, TonEBP induces transcription of genes involved in matrix homeostasis (green) (ACAN, GlcAT-I, AQP2, Sox9) to autoregulate the extracellular osmotic environment. In the pathological state, activation of TLR or NF-κB pathways induce TonEBP to act on a specific set of targets (red). Activity on osmoadaptation targets (blue) is decreased with this type of activation. Osmotic stress may also induce TonEBP activation of pro-inflammatory targets (green). It should be noted that in disc and cartilage relationship between pathological stimuli and TonEBP has not been studied yet. *Studies have not addressed whether TonEBP binds TonE in Sox9. AR, aldose reductase; BGT1, betaine-g-amino butyric acid transporter; SMIT, sodium myo-inositol transporter; TauT, taurine transporter (TauT); ACAN, Aggrecan; GlcAT-I, β1,3-glucuronosyl transferase 1; AQP2, Aquaporin 2; TLR, Toll-like receptor; TNF-a, tumor necrosis factor-a; IL-6, interleukin 6;NOS2, nitric oxide synthase 2; VCAN, versican; MMP-13, matrix metallopeptidase 13. Targets in dashed border indicate results that have not been verified in NP cells or chondrocytes.
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Figure 2: Schematic representation of the osmotic response in healthy (left panel) and degenerative (right panel) disc or articular cartilage tissues. In healthy tissue, hyperosmolarity results from high negative charge of proteoglycans resulting in influx of NaCl. Hyperosmolarity results in robust increase in TonEBP mRNA, protein, and nuclear shuttling. TonEBP binds to TonE sites in target promoters to drive expression of osmotic response genes (blue) (AR, BGT1, SMIT, TauT), protecting against cellular damage during hypertonic stress. Similarly, TonEBP induces transcription of genes involved in matrix homeostasis (green) (ACAN, GlcAT-I, AQP2, Sox9) to autoregulate the extracellular osmotic environment. In the pathological state, activation of TLR or NF-κB pathways induce TonEBP to act on a specific set of targets (red). Activity on osmoadaptation targets (blue) is decreased with this type of activation. Osmotic stress may also induce TonEBP activation of pro-inflammatory targets (green). It should be noted that in disc and cartilage relationship between pathological stimuli and TonEBP has not been studied yet. *Studies have not addressed whether TonEBP binds TonE in Sox9. AR, aldose reductase; BGT1, betaine-g-amino butyric acid transporter; SMIT, sodium myo-inositol transporter; TauT, taurine transporter (TauT); ACAN, Aggrecan; GlcAT-I, β1,3-glucuronosyl transferase 1; AQP2, Aquaporin 2; TLR, Toll-like receptor; TNF-a, tumor necrosis factor-a; IL-6, interleukin 6;NOS2, nitric oxide synthase 2; VCAN, versican; MMP-13, matrix metallopeptidase 13. Targets in dashed border indicate results that have not been verified in NP cells or chondrocytes.

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).


Extracellular osmolarity regulates matrix homeostasis in the intervertebral disc and articular cartilage: evolving role of TonEBP.

Johnson ZI, Shapiro IM, Risbud MV - Matrix Biol. (2014)

Schematic representation of the osmotic response in healthy (left panel) and degenerative (right panel) disc or articular cartilage tissues. In healthy tissue, hyperosmolarity results from high negative charge of proteoglycans resulting in influx of NaCl. Hyperosmolarity results in robust increase in TonEBP mRNA, protein, and nuclear shuttling. TonEBP binds to TonE sites in target promoters to drive expression of osmotic response genes (blue) (AR, BGT1, SMIT, TauT), protecting against cellular damage during hypertonic stress. Similarly, TonEBP induces transcription of genes involved in matrix homeostasis (green) (ACAN, GlcAT-I, AQP2, Sox9) to autoregulate the extracellular osmotic environment. In the pathological state, activation of TLR or NF-κB pathways induce TonEBP to act on a specific set of targets (red). Activity on osmoadaptation targets (blue) is decreased with this type of activation. Osmotic stress may also induce TonEBP activation of pro-inflammatory targets (green). It should be noted that in disc and cartilage relationship between pathological stimuli and TonEBP has not been studied yet. *Studies have not addressed whether TonEBP binds TonE in Sox9. AR, aldose reductase; BGT1, betaine-g-amino butyric acid transporter; SMIT, sodium myo-inositol transporter; TauT, taurine transporter (TauT); ACAN, Aggrecan; GlcAT-I, β1,3-glucuronosyl transferase 1; AQP2, Aquaporin 2; TLR, Toll-like receptor; TNF-a, tumor necrosis factor-a; IL-6, interleukin 6;NOS2, nitric oxide synthase 2; VCAN, versican; MMP-13, matrix metallopeptidase 13. Targets in dashed border indicate results that have not been verified in NP cells or chondrocytes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 2: Schematic representation of the osmotic response in healthy (left panel) and degenerative (right panel) disc or articular cartilage tissues. In healthy tissue, hyperosmolarity results from high negative charge of proteoglycans resulting in influx of NaCl. Hyperosmolarity results in robust increase in TonEBP mRNA, protein, and nuclear shuttling. TonEBP binds to TonE sites in target promoters to drive expression of osmotic response genes (blue) (AR, BGT1, SMIT, TauT), protecting against cellular damage during hypertonic stress. Similarly, TonEBP induces transcription of genes involved in matrix homeostasis (green) (ACAN, GlcAT-I, AQP2, Sox9) to autoregulate the extracellular osmotic environment. In the pathological state, activation of TLR or NF-κB pathways induce TonEBP to act on a specific set of targets (red). Activity on osmoadaptation targets (blue) is decreased with this type of activation. Osmotic stress may also induce TonEBP activation of pro-inflammatory targets (green). It should be noted that in disc and cartilage relationship between pathological stimuli and TonEBP has not been studied yet. *Studies have not addressed whether TonEBP binds TonE in Sox9. AR, aldose reductase; BGT1, betaine-g-amino butyric acid transporter; SMIT, sodium myo-inositol transporter; TauT, taurine transporter (TauT); ACAN, Aggrecan; GlcAT-I, β1,3-glucuronosyl transferase 1; AQP2, Aquaporin 2; TLR, Toll-like receptor; TNF-a, tumor necrosis factor-a; IL-6, interleukin 6;NOS2, nitric oxide synthase 2; VCAN, versican; MMP-13, matrix metallopeptidase 13. Targets in dashed border indicate results that have not been verified in NP cells or chondrocytes.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA, United States.

Show MeSH
Related in: MedlinePlus