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A10.26 Synovial Wnt and WISP1 Expression Induces Expression of Cartilage-Degrading Metalloproteinases in the Synovium
  1. M van den Bosch,
  2. A Blom,
  3. A van Erp,
  4. F van de Loo,
  5. E Blaney Davidson,
  6. P van der Kraan,
  7. P van Lent,
  8. W van den Berg
  1. Radboud University Nijmegen Medical Centre, NCMLS, Nijmegen, Netherlands

Abstract

Background Many osteoarthritis (OA) patients show synovial involvement. We found strong upregulation of Wnts 2b and 16 and the downstream protein WISP1 in knee joints in experimental OA. The role of the synovium in the induction of OA pathology under the influence of Wnt signalling is unclear. Here we investigated the potential of Wnt signalling 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 vivo synovial overexpression of genes from the canonical Wnt signalling pathway was achieved by intra-articular injection of adenoviral vectors. Joint pathology was assessed by histology. Gene expression was analysed by qPCR. Human OA synovial specimens were collected from joint replacement surgery and stimulated or used for outgrowth of fibroblasts.

Results Pathway analysis showed that the Wnt signalling pathway was enriched in the synovium during experimental OA. To determine the effects of Wnt signalling 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 TIMP1 and 3 was not altered. Next, we investigated which cell-type in the synovium may cause the increased MMP expression. Stimulation of synovial OA fibroblasts with Wnt3a increased the expression of MMP3 and MMP13, whereas WISP1 led to increased MMP3 expression. Stimulation of THP-1 cells with Wnt3a resulted in highly increased MMP3, MMP9 and MMP13 expression. WISP1 stimulation led to increased expression of MMP3. TIMP1 and 3 expression was not altered. Synovial overexpression of Wnt8a, Wnt16 and WISP1 in murine knee joints with use of adenoviral vectors led to cartilage damage in vivo. 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. In addition, overexpression of WISP1 led to significantly increased cartilage damage after 7 days.

Conclusions Canonical Wnts produced in the synovium may play an important role in OA pathology by increasing the expression of cartilage-degrading MMPs in synovial tissue, where fibroblasts and macrophages showed comparable patterns of MMP induction. Synovium-specific overexpression of Wnt signalling members induces cartilage damage.

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