OP0068 Wisp1 Induces Pathology in Experimental Osteoarthritis and Predicts Disease Progression in Early Osteoarthritis Patients
Authors: M. van den Bosch, A. Blom, A. Maeda, T. Kilts, W. van den Berg, P. van Lent, M. Young, P. van der Kraan
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Many osteoarthritis (OA) patients show synovial activation, which is suggested to be involved in joint destruction. Previously, we found strong upregulation of <i>Wnt2b</i> and <i>Wnt16</i> in the synovium of two experimental OA models. In addition, we found strongly increased <i>Wisp1</i> expression, a protein induced by canonical Wnt signaling. <h3>Objectives</h3> To determine whether there is a relation between <i>WISP1</i> expression and progression of OA in a cohort study of patients with early symptomatic OA. Furthermore, we will elucidate whether WISP1 plays a role during experimental OA by inducing OA models in wild type (WT) and <i>Wisp1</i><sup>–/–</sup> mice. <h3>Methods</h3> Microarray analysis was performed on synovium from patients enrolled in the CHECK study, initiated to follow the progression of early symptomatic OA patients. Expression data were correlated with progression of OA (defined as a decrease in joint space width of ≥1mm and progression of osteophyte formation of ≥4x in size) between baseline and the five-year follow-up measurement. Human end-stage OA synovium was stimulated with WISP1. Joint pathology in WT or <i>Wisp1</i><sup>–/–</sup> mice was assessed by histology after induction of collagenase-induced OA (CIOA), destabilization of the medial meniscus (DMM) and anterior cruciate ligament transection (ACLT) experimental models of OA. The aggrecan neoepitope NITEGE was visualized using immunohistochemistry. Gene expression in the synovial tissue was evaluated using qRT-PCR. <h3>Results</h3> Microarray analysis of synovial tissue from patients in the CHECK cohort showed significantly increased WISP1 expression at baseline in OA progressors versus non-progressors. To determine the mechanism of how WISP1 might be involved in OA pathology, we stimulated human OA synovium with WISP1. This increased the expression of <i>MMP2/3/9/13</i> and <i>ADAMTS4/5</i>. Next, we determined the <i>in vivo</i> role of WISP1. First, we found that spontaneous cartilage damage was not different between WT and <i>Wisp1</i><sup>–/–</sup> mice at 3, 6 and 12 months of age. Next, we assessed joint pathology 42 days after induction of CIOA in WT and <i>Wisp1</i><sup>–/–</sup> mice. Cartilage damage was significantly decreased in the tibio-femoral joints of the <i>Wisp1</i><sup>–/–</sup> mice as compared with the WT controls. In line with the CIOA, we found significantly decreased cartilage degeneration in the <i>Wisp1</i><sup>–/–</sup> mice in the DMM and ACLT at day 56 after induction. In addition we found decreased expression of <i>Mmp3</i>/<i>9</i> and the aggrecanases <i>Adamts4/5</i> in the synovium, 7 days after induction of CIOA in <i>Wisp1</i><sup>–/–</sup> mice, in line with the increased expression of these factors after stimulation of human OA synovium with WISP1. Furthermore, the expression of the protease inhibitor <i>Timp1</i> was decreased in the <i>Wisp1</i><sup>–/–</sup> mice, whereas the expression of <i>Timp3</i>, an important inhibitor of ADAMTS-4/5, was unaffected. Finally, the protease activity in the cartilage, as assessed by the staining of the neoepitope NITEGE, was decreased in the <i>Wisp1</i><sup>–/–</sup> mice. <h3>Conclusions</h3> Increased WISP1 expression may play an important role in OA pathology via increased synovial MMP/ADAMTS expression. Furthermore, because of the tight regulation and complexity of Wnt signaling and its role in many physiological processes, targeting WISP1 may more specifically target the OA-related pathological events, while minimizing interference with physiological processes. <h3>Disclosure of Interest</h3> None declared