Article Text

PDF
A5.8 Synovial wnt and wisp1 expression induces expression of cartilage-degrading metalloproteinases in the synovium
  1. M H van den Bosch,
  2. A B Blom,
  3. S W F Suen,
  4. A E van Erp,
  5. F A van de Loo,
  6. E N Blaney Davidson,
  7. P M van der Kraan,
  8. P L van Lent,
  9. W B van den Berg
  1. Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands

Abstract

Background Consequences of synovial activation, seen in many OA patients, are largely unknown. Previously, we found strong upregulation of various members of the Wnt signalling pathway in knee joints of two experimental OA models. Wnt signalling has been implicated in OA incidence via activation of β-catenin. 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. In vivo synovial overexpression of genes 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 and either stimulated or used for outgrowth of OA fibroblasts. Human macrophages were differentiated from monocytes, isolated from buffy-coats.

Results Pathway analysis using DAVID showed enrichment of Wnt signalling 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, a downstream protein of canonical Wnt signalling, which resulted in increased expression of various MMPs. Contrastingly, the expression of TIMPs, inhibitors of MMPs, was not altered. Blocking Wnt signalling with specific inhibitors decreased the MMP expression. Next, we investigated which cell type in the synovium may cause the increased MMP expression. Stimulation of human synovial OA fibroblasts with Wnt3a or WISP1 increased the expression of MMPs, whereas stimulation of M1 and M2 macrophages did not. However, Wnt signalling strongly upregulated the MMP expression in monocytes, whereas TIMP levels remained unchanged. To determine if synovial overexpression of members of the Wnt signalling pathway leads to cartilage damage in vivo, we injected adenoviral vectors for Wnt8a, Wnt16 and WISP1 into murine knee joints. These vectors, due to their size, specifically target synovial cells and not cartilage. Seven days after overexpression, we found a significant induction of OA pathology. 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.

Conclusions Canonical Wnts produced in the synovium may play an important role in OA pathology by increasing the production of MMPs in the synovium. Overexpression of Wnt signalling members, as is found in experimental OA, induces cartilage damage in vivo. This underlines synovial Wnt and WISP1 expression to be potential targets for OA therapy.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.