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Abstract Number: 769

Synovial Wnt and WISP1 Expression Induces Expression Of Cartilage-Degrading Metalloproteinases In The Synovium

Martijn H. van den Bosch1, Arjen B. Blom1, Sylvia W. Suen2, Anke E. van Erp2, Fons A. van de Loo3, Esmeralda N. Blaney Davidson1, Peter M. van der Kraan3, Peter L. van Lent4 and Wim B. van den Berg5, 1Rheumatology Research & Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 2Experimental Rheumatology, Radboud university medical center, Nijmegen, Netherlands, 3Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 4Rheumatology Research & Advanced Therpeutics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 5Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: cartilage, osteoarthritis and synovitis, WNT Signaling

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Session Information

Title: Biology and Pathology of Bone and Joint I: Cartilage Biology and Osteoarthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Although many osteoarthritis (OA) patients show significant synovial involvement, consequences are largely unknown. Previously, we found strong upregulation of Wnts 2b and 16 and WISP1, a downstream protein of canonical Wnt signaling, in knee joints in two murine OA models. Wnt signaling has been implicated in OA incidence and modulation of the β-catenin pathway leads to OA-like changes in cartilage. However, the role of the synovium in the induction of OA pathology under the influence of Wnt signaling is unclear. Here we investigated the potential of Wnt signaling to increase the expression of cartilage-degrading enzymes in the synovium.

Methods: Pathway analysis of microarray data from the synovium of a collagenase-induced OA mouse model was done using DAVID software. In vivosynovial overexpression of genes from the canonical Wnt signaling pathway was achieved by intra-articular injection of adenoviral vectors. Joint pathology was assessed by histology at several time points after injection. Gene expression was analyzed by qPCR. Human OA synovial specimen were collected from joint replacement surgery and either stimulated or used for outgrowth of OA fibroblasts.

Results: Pathway analysis using DAVID showed that Wnt signaling was enriched in the synovium during experimental OA. To determine the effects of Wnt signaling on synovial tissue, we stimulated human OA synovial specimen with Wnt3a or WISP1, which resulted in increased expression of MMP3, MMP9 and MMP13, whereas expression of the MMP inhibitors TIMP1 and 3 was not altered. Next, we investigated which cell type in the synovium may cause the increased MMP expression. Stimulation of human synovial OA fibroblasts with Wnt3a increased the expression of both MMP3 and MMP13, whereas stimulation of these cells with WISP1 led to an upregulation of MMP3. Stimulation of human THP-1 cells with Wnt3a resulted in highly increased expression of MMP3, MMP9 and MMP13. Stimulation with WISP1 led to increased expression of MMP3. Expression levels of TIMP1 and TIMP3 were not altered. To determine if synovial overexpression of members of the Wnt signaling pathway leads to cartilage damage in vivo, we injected adenoviral vectors for Wnt8a, Wnt16 and WISP1 into murine knee joints. These vectors specifically target synovial cells, due to their size. 7 days after overexpression, we found a significant induction of OA pathology at the medial margin of the medial tibial plateau, a preferential site for damage in experimental OA. Lesions were found in 92% (n=12) of the knee joints after Wnt8a overexpression compared to 17% (N=12) for the control virus and 80% (N=5) for Wnt16 overexpression, but only 20% (N=5) for the control virus. 

Conclusion: Canonical Wnts produced in the synovium may play an important role in OA pathology. Stimulation of human OA synovium with Wnts and WISP1 increases the expression of MMPs. Fibroblasts and macrophages showed comparable patterns of MMP induction. In addition, synovium specific overexpression of Wnt signaling members, as is found in experimental OA, induces cartilage damage in vivo. This underlines synovial Wnt/WISP1 expression to be a potential target for OA therapy.


Disclosure:

M. H. van den Bosch,
None;

A. B. Blom,
None;

S. W. Suen,
None;

A. E. van Erp,
None;

F. A. van de Loo,
None;

E. N. Blaney Davidson,
None;

P. M. van der Kraan,
None;

P. L. van Lent,
None;

W. B. van den Berg,
None.

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