Background/Purpose: Many osteoarthritis (OA) patients show synovial activation, which is suggested to be involved in joint destruction. Previously, we found synovial overexpression of Wnt ligands in experimental OA models. In addition, we found increased expression of WISP1, a downstream protein of canonical Wnt signaling, in both synovium and cartilage. In this study we investigated the role of WISP1 in experimental OA models in WISP1 KO mice and determined if WISP1 was involved in progression of early human OA.

Methods: Pathway analysis of microarray data from the synovium of a collagenase-induced OA (CIOA) and destabilization of the medial meniscus (DMM) model was performed using DAVID bioinformatics software. Microarray analysis was performed on synovial tissue of patients with early complaints of knee or hip pain, enrolled in the CHECK study. Expression data was correlated with progression between baseline and the five-year follow-up measurement. Progression was defined as decreased joint space width of at least 1 mm and progression of osteophyte formation of at least 4x in size. CIOA, DMM and anterior cruciate ligament transection (ACLT) experimental OA models were induced in WT and WISP1 knockout mice. Joint pathology was assessed by histology. Human OA synovium was obtained after joint replacement surgery and stimulated with WISP1. Smad phosphorylation and β-catenin accumulation were determined using immunohistochemistry.

Results: Pathway analysis showed enrichment of Wnt signaling in both the CIOA and DMM at various time points. In addition, microarray analysis of synovial tissue from patients in the CHECK study showed that WISP1 expression was correlated with the progression of OA between baseline and the five-year follow-up measurement. To further pinpoint the role of WISP1 in the etiopathology of OA, we induced experimental OA in WT and WISP1 KO mice. We found significantly decreased cartilage damage in the knee joints of WISP1 KO mice in three models of experimental OA. Synovium of WISP1 KO mice showed reduced expression of MMPs, which is in line with our finding that stimulation of human OA synovium with WISP1 increased the MMP expression. TGF-β signaling via Smad 2/3 is crucial for maintaining cartilage homeostasis, while signaling via Smad 1/5/8 is associated with chondrocyte hypertrophy. To determine if WISP1 affects TGF-β signaling, we stained WT and WISP1 depleted joints for phosphorylated Smad 2/3 and found increased pSmad 2/3 in the WISP1 KO mice. In addition, recent data showed that WISP1 could regulate the accumulation of β-catenin, and positively control canonical Wnt signaling, further aggravating the OA pathology. Staining for β-catenin indeed showed that WISP1 depleted joints have decreased levels of β-catenin accumulation in the cartilage.

Conclusion: Overexpression of WISP1 in the joint may play an important role in OA pathology via modulation of TGF-β signaling and positive feedback on canonical Wnt signaling. Targeting upstream Wnt signaling likely causes undesired side effects, as the pathway is extremely complex and involved in many processes. Specific downregulation of WISP1 may more specifically target pathological events that take place during OA without interfering with normal processes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/wisp1-aggravates-osteoarthritis-by-modulation-of-tgf-signaling-and-positive-regulation-of-canonical-wnt-signaling/