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Abstract Number: 51

Phosphodiesterase 4 Expression in Rheumatoid Arthritis Synovium and Anti-Inflammatory Effects of Apremilast On Synovial Fibroblasts

Lei Wu, Mary Adams, Stacey Parton and Peter Schafer, Department of Translational Development, Celgene Corporation, Summit, NJ

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: matrix metalloproteinase (MMP), rheumatoid arthritis (RA) and synovial cells, synovial fluid

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Session Information

Title: Biology and Pathology of Bone and Joint

Session Type: Abstract Submissions (ACR)

Background/Purpose: Apremilast (APR), a small molecule specific inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate pro- and anti-inflammatory mediator production in both immune and non-immune cells. The expression pattern of the major PDE4 enzymes was studied in rheumatoid arthritis (RA) synovium, in normal and RA synovial fibroblasts (RASF), and the effects of APR on the production of major destructive proteases by RASF were examined.

Methods: PDE4 protein expression was measured by semiquantitative immunohistochemistry (IHC) in synovium from individuals with RA (n=3) or normal controls (n=2). Quantitative analysis of PDE4 protein expression in normal (n=3) and RASF (n=3) was conducted using an iCyte Laser Scanning Cytometer. Gene expression in normal synovial fibroblasts (n=3), RASF (n=3), peripheral blood mononuclear cells from RA (n=10) and normal controls (n=10) was measured by qRT-PCR. RASF cell cultures (n=3) were treated with 0.1-10 µM APR and then stimulated with 10 ng/mL IL-1β, TNF-α, IL-17, or IL-6 for a total of 24 hours, then supernatants were collected for analysis of matrix metalloproteinase (MMP)1, MMP13, MMP14, and cathepsin K by ELISA.

Results: IHC staining of synovial samples showed that, compared with normal samples, the superficial synoviocytes and subsynovial histiocytes in RA samples had more prevalent and more intense staining of PDE4A, PDE4B, and PDE4D. PDE4B staining was slightly higher in fibroblasts from RA patients than controls, while PDE4D staining was slightly lower. Laser scanning cytometry of normal synovial fibroblasts and RASF showed similar strong cytoplasmic staining of PDE4A in normal and RA samples. PDE4B showed abundant cytoplasmic staining, with 45% higher staining in RASF compared with controls (p<0.01). PDE4D showed moderate to strong cytoplasmic staining in normal samples, but 45% weaker expression in RASF samples (p<0.05). qRT-PCR analysis of PDE4A and PDE4B gene expression was similar in RASF and controls, but PDE4D gene expression was 60% lower in RASF compared with controls (p<0.01). In RASF cell cultures stimulated with IL-1β or TNF-α, APR significantly inhibited MMP1 and MMP14 production, while in the IL-17- or IL-6-stimulated cultures, no significant inhibition of these proteases was observed.

Conclusion: Overall, PDE4 protein expression was stronger in RA vs. normal synovium, largely due to increases in superficial synoviocytes, subsynovial histiocytes, and lymphoplasmacytic cells. In RASF, there is a shift in expression away from PDE4D toward PDE4B, and APR is capable of inhibiting MMP production in response to the JAK-independent stimuli, IL-1β and TNF-α. This study provides the preclinical rationale for using APR in RA.


Disclosure:

L. Wu,

Celgene,

3;

M. Adams,

Celgene,

3;

S. Parton,

Celgene,

3;

P. Schafer,

Celgene,

3.

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