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Dexamethasone Attenuates the Expression of MMP-13 in Chondrocytes through MKP-1
Tiina Lehtola1, Elina Nummenmaa1, Lauri Tuure1
1The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland.
Abstract:
Mitogen-activated protein kinase phosphatase-1 (MKP-1) is upregulated in inflammation and reduces the activity of proinflammatory mitogen-activated protein kinases (MAP kinases) by dephosphorylation. MAP kinases are intracellular signaling pathways that mediate the cellular effects of proinflammatory cytokines. In the present study, we investigated the effects of the glucocorticoid dexamethasone on the expression of catabolic enzymes in chondrocytes and tested the hypothesis that these effects are mediated through MKP-1. Dexamethasone was found to significantly attenuate the expression of matrix metalloproteinase (MMP)-13 in human OA chondrocytes as well as in chondrocytes from MKP-1 WT mice, but not in chondrocytes from MKP-1 KO mice. Dexamethasone also increased the expression of MKP-1 in murine and human OA chondrocytes. Furthermore, p38 MAP kinase inhibitors significantly attenuated MMP-13 expression in human OA chondrocytes, while JNK MAP kinase inhibitors had no effect. The results indicate that the effect of dexamethasone on MMP-13 expression in chondrocytes was mediated by an MKP-1 and p38 MAP kinase-dependent manner. These findings, together with previous results, support the concept of MKP-1 as a protective factor in articular chondrocytes in inflammatory conditions and as a potential drug target to treat OA.
Insights
Dexamethasone reduces matrix metalloproteinase-13 (MMP-13) in osteoarthritis chondrocytes via Mitogen-activated protein kinase phosphatase-1 (MKP-1) and p38 MAP kinase. This suggests MKP-1 is a protective factor and potential therapeutic target for osteoarthritis.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Mitogen-activated protein kinase phosphatase-1 (MKP-1) is upregulated during inflammation.
- MKP-1 dephosphorylates and reduces the activity of pro-inflammatory mitogen-activated protein kinases (MAPKs).
- MAPK signaling pathways mediate cellular responses to pro-inflammatory cytokines.
Purpose of the Study:
- To investigate the effects of dexamethasone on catabolic enzyme expression in chondrocytes.
- To test the hypothesis that dexamethasone's effects are mediated through MKP-1.
- To elucidate the role of MKP-1 and specific MAPKs in dexamethasone-induced modulation of MMP-13.
Main Methods:
- Studied dexamethasone's effect on matrix metalloproteinase (MMP)-13 expression in human osteoarthritis (OA) chondrocytes and MKP-1 wild-type (WT) and knockout (KO) murine chondrocytes.
- Assessed MKP-1 expression in response to dexamethasone in human and murine OA chondrocytes.
- Utilized p38 and JNK MAP kinase inhibitors to evaluate their impact on MMP-13 expression.
Main Results:
- Dexamethasone significantly attenuated MMP-13 expression in human OA chondrocytes and MKP-1 WT mouse chondrocytes, but not in MKP-1 KO chondrocytes.
- Dexamethasone increased MKP-1 expression in both human and murine OA chondrocytes.
- p38 MAP kinase inhibitors, but not JNK inhibitors, significantly reduced MMP-13 expression in human OA chondrocytes.
Conclusions:
- Dexamethasone's inhibitory effect on MMP-13 expression in chondrocytes is dependent on MKP-1 and p38 MAP kinase.
- MKP-1 acts as a protective factor in articular chondrocytes during inflammatory conditions.
- MKP-1 represents a potential therapeutic target for the treatment of osteoarthritis.
