Dual specificity phosphatase 1 is a crucial negative
Dual specificity phosphatase 1 is a crucial negative
Dual specificity phosphatase 1 is a crucial negative
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Dusp1 regulates inflammatory<br />
osteolys<strong>is</strong> and therapeutic effects of<br />
dexamethasone in CIA<br />
Youridies Vattakuzhi<br />
Kennedy Institute of Rheumatology<br />
Presenter D<strong>is</strong>closure Information:<br />
no conflicts of interest
<strong>Dual</strong> Specificity Phosphatase 1 (DUSP1)<br />
• DUSP1 (MKP-1) inactivates MAPKs by dephosphorylation<br />
of threonine and tyrosine residues in the activation loop of<br />
p38 MAPK and JNK<br />
• MAPK activation triggers pro-inflammatory cytokines<br />
• Enhanced inflammation in Dusp1 -/- mice<br />
• Zymosan induced inflammation (Abraham et al. 2006)<br />
• LPS challenge (Carlson et al. 2009)<br />
• Periodontal d<strong>is</strong>ease (Yu et al. 2010)
DUSP1 activation in osteoclasts<br />
• RANKL activates p38 MAPK<br />
• RANKL induces Dusp1 expression (Carlson et al. 2009)<br />
Dusp1 +/+ Dusp1 -/- DUSP1<br />
Carlson et al. 2009
Resorption area (mm 2 /slice)<br />
TRAP positive mnc/well<br />
Enhanced osteoclastogenes<strong>is</strong> in Dusp1 -/-<br />
mice<br />
Dusp1 +/+<br />
M-CSF<br />
RANKL<br />
M-CSF<br />
RANKL<br />
TNFα<br />
400<br />
300<br />
200<br />
Dusp1 +/+<br />
Dusp1 -/-<br />
*<br />
n.s.<br />
***<br />
***<br />
100<br />
Dusp1 -/-<br />
0<br />
M-CSF (25ng/ml)<br />
RANKL (5ng/ml)<br />
TNF (2pg/ml)<br />
0.20<br />
0.15<br />
Dusp1 +/+<br />
0.10<br />
0.05<br />
Dusp1 -/-<br />
0.00<br />
M-CSF (25ng/ml)<br />
200µm RANKL (5ng/ml)<br />
TNF (2pg/ml)<br />
+ +<br />
+ +<br />
n.s.<br />
+ +<br />
+ +<br />
n.s.<br />
*<br />
+ +<br />
+ +<br />
+ +<br />
**<br />
+ +<br />
+ +<br />
+ +
Collagen Induced Arthrit<strong>is</strong><br />
• TNFα drives inflammation and bone resorption in RA<br />
• Enhanced osteoclast activity <strong>is</strong> a debilitating feature of<br />
rheumatoid arthrit<strong>is</strong> (RA)<br />
• Immunization with chicken collagen type 2 and<br />
complete Freund’s adjuvant
Early onset and increased incidence of<br />
CIA in Dusp1 -/- mice
Increased severity in Dusp1 -/- mice<br />
• Synovial hyperplasia<br />
• Inflammatory infiltrate<br />
• Bone erosions<br />
• Cartilage damage
Increased bone resorption in Dusp1 -/- mice<br />
Dusp1 +/+ Dusp1 -/-<br />
Naive<br />
CIA<br />
Naive<br />
CIA
Adaptive immune responses in CIA<br />
• TNFα and IL-17 promote osteoclast activity in CIA<br />
• Th17<br />
• Th1<br />
• Th2<br />
• Secretion of pro-inflammatory IL-17<br />
• Secretion of IFNγ<br />
• Promote collagen specific Ab production by B cells (IgG2a)<br />
• Promote collagen specific Ab production by B cells (IgG1)
Increased IL-17 production in Dusp1 -/-<br />
mice<br />
0.152%<br />
Dusp1 +/+<br />
0.358%<br />
CD4 +<br />
IL-17 + Dusp1 -/-
elative to control<br />
Decreased anti-collagen IgG2a in<br />
Dusp1 -/- mice<br />
5 Dusp1 +/+ (PBS)<br />
4<br />
Dusp1 -/- (PBS)<br />
**<br />
3<br />
n.s.<br />
2<br />
1<br />
0<br />
IgG1<br />
IgG2a<br />
• Reduced Th1 cell activity<br />
• Enhanced IL-17 production from Th17 cells
Can dexamethasone reduce<br />
inflammation in arthritic Dusp1 -/- mice?<br />
• Glucocorticoids are potent anti-inflammatory drugs (e.g.<br />
inactivates MAPKs)<br />
• Expression of Dusp1 can be induced by glucocorticoids<br />
(Lasa et al. 2002)<br />
• Dexamethasone (Dex) induced inactivation of MAPK <strong>is</strong><br />
partly mediated by activation of DUSP1<br />
• i.p. injection of 0.5mg/kg Dex every 2 days after onset of<br />
d<strong>is</strong>ease
Dex treatment reduced clinical scores in<br />
arthritic Dusp1 +/+ mice<br />
↓42%<br />
↓17%
Reduced effect of Dex on T cell<br />
proliferation in Dusp1 -/- mice<br />
• Dex had no effect on IFNγ, IL-17 or collagen-specific Ab<br />
production<br />
in vitro<br />
in vivo<br />
n.s.
DUSP1 regulates bone resorption and<br />
inflammation in CIA<br />
Dusp1 -/-<br />
↓p38 MAPK<br />
Dexamethasone<br />
↑ TNFα ↑ resorption ↑ ↓ activation proliferation<br />
Macrophage Osteoclast T h17 T cell<br />
Abraham et al. 2006 Vattakuzhi et al. 2012<br />
↑ TNFα<br />
Dusp1 -/- Dusp1 -/-<br />
↑ IL-17<br />
↓p38 MAPK<br />
Dexamethasone<br />
↑↑ RESORPTION<br />
INFLAMMATION
Acknowledgements<br />
• Nikki Horwood and Andy Clark<br />
• Richard Williams<br />
• Andrew Freidin<br />
Original Dusp1 -/- mice from: