Session Type: Abstract Submissions (ACR)
Background/Purpose: Many osteoarthritis (OA) patients show synovial activation, which is thought to be involved in joint destruction. Previously, we found that the alarmins S100A8 and A9, and various members of the Wnt signaling pathway, including Wnt16, were highly increased in the synovium of knee joints during experimental OA. WISP1, a downstream protein of β-catenin-dependent canonical Wnt signaling, was increased in both synovium and cartilage. S100A9KO mice showed strongly reduced pathology in experimental OA. Wnt signaling has been linked to OA through activation of β-catenin, but the role of the synovium in OA pathology under the influence of Wnt signaling is unclear. In this study we investigated whether S100 proteins induce Wnt signaling and determined the potency of Wnts to increase expression of cartilage-degrading enzymes in the synovium.
Methods: Pathway analysis of microarray data from synovium of a collagenase-induced OA was done using DAVID. Activation of Wnt signaling was determined with β-catenin immunostaining of whole knee joint sections. Gene expression was analyzed by qPCR. Human OA synovial specimens were collected from joint replacement surgery and stimulated with S100 or members of the Wnt signaling pathway or blocked with the Wnt inhibitors FrzB and DKK-1.
Results: Pathway analysis showed enrichment of Wnt signaling in the synovium during experimental OA. Because upregulation of both S100 and Wnt proteins during experimental OA showed comparable kinetics, we determined if S100 proteins could induce Wnt signaling. We found that injections of S100A8 into mouse knee joints led to increased expression of Wnt16 and WISP1 in the synovium and β-catenin accumulation in the joint. Underlining an interrelationship between Wnt signaling and S100A8/9, we found less β-catenin accumulation during experimental OA in S100A9KO mice. To determine the effects of canonical Wnt signaling in the synovium, we overexpressed Wnt16 and WISP1 in the synovium with adenoviral vectors. This resulted in increased expression of various MMPs in the synovium. To translate these finding to a human situation, we stimulated human OA synovial tissues with Wnt3a, as a model for a canonical Wnt, and WISP1. This led to significantly increased expression of MMP3, MMP9 and MMP13, whereas the expression of the MMP inhibitors TIMP1 and 3 was not altered. Next, we hypothesized that if Wnt signaling was increased in OA synovium and that stimulation of synovium with members of the Wnt signaling pathway led to increased expression of various MMPs, that we should be able to decrease the expression of MMPs by blocking the Wnt signaling pathway. Inhibition of Wnt signaling by both FrzB, a general Wnt inhibitor, and DKK-1, selectively blocking canonical Wnt signaling, led to significantly decreased expression of MMPs.
Conclusion: S100 proteins are able to increase Wnt signaling. 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, whereas blocking Wnt signaling results in decreased expression of MMPs. This underlines synovial Wnt/WISP1 expression to be a potential target for OA therapy.
M. H. van den Bosch,
A. B. Blom,
R. P. Hoek,
R. F. Schelbergen,
S. W. Suen,
A. E. van Erp,
W. B. van den Berg,
P. M. van der Kraan,
P. L. van Lent,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/s100-proteins-induce-canonical-wnt-signaling-which-causes-increased-expression-of-mmps-in-the-synovium/