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Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis
Caressa Lietman, Brian Wu, Sarah Lechner, Andrew Shinar, Madhur Sehgal, Evgeny Rossomacha, Poulami Datta, Anirudh Sharma, Rajiv Gandhi, Mohit Kapoor, Pampee P. Young
Caressa Lietman, Brian Wu, Sarah Lechner, Andrew Shinar, Madhur Sehgal, Evgeny Rossomacha, Poulami Datta, Anirudh Sharma, Rajiv Gandhi, Mohit Kapoor, Pampee P. Young
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Research Article Aging Inflammation

Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis

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Abstract

Osteoarthritis (OA) is a degenerative joint disease involving both cartilage and synovium. The canonical Wnt/β-catenin pathway, which is activated in OA, is emerging as an important regulator of tissue repair and fibrosis. This study seeks to examine Wnt pathway effects on synovial fibroblasts and articular chondrocytes as well as the therapeutic effects of Wnt inhibition on OA disease severity. Mice underwent destabilization of the medial meniscus surgery and were treated by intra-articular injection with XAV-939, a small-molecule inhibitor of Wnt/β-catenin signaling. Wnt/β-catenin signaling was highly activated in murine synovial fibroblasts as well as in OA-derived human synovial fibroblasts. XAV-939 ameliorated OA severity associated with reduced cartilage degeneration and synovitis in vivo. Wnt inhibition using mechanistically distinct small-molecule inhibitors, XAV-939 and C113, attenuated the proliferation and type I collagen synthesis in synovial fibroblasts in vitro but did not affect human OA-derived chondrocyte proliferation. However, Wnt modulation increased COL2A1 and PRG4 transcripts, which are downregulated in chondrocytes in OA. In conclusion, therapeutic Wnt inhibition reduced disease severity in a model of traumatic OA via promoting anticatabolic effects on chondrocytes and antifibrotic effects on synovial fibroblasts and may be a promising class of drugs for the treatment of OA.

Authors

Caressa Lietman, Brian Wu, Sarah Lechner, Andrew Shinar, Madhur Sehgal, Evgeny Rossomacha, Poulami Datta, Anirudh Sharma, Rajiv Gandhi, Mohit Kapoor, Pampee P. Young

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Figure 4

Proliferation of synovial fibroblasts is elevated in OA and can be moderated through Wnt inhibition.

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Proliferation of synovial fibroblasts is elevated in OA and can be moder...
(A) Immunohistochemistry of Ki-67 on knee synovia from saline control and Wnt inhibitor mice 10 weeks after surgery showed a reduction in proliferation of synovial fibroblasts after treatment with Wnt inhibitor. Original magnification, ×20 (top); ×40 (bottom). (B) Knee synovia were stained by immunofluorescence with periostin (POSTN, green) and PCNA (red), a proliferating cell marker, and counterstained with nuclear DAPI (blue). The joint region used for immunofluorescence is shown by H&E stain. Synovia from saline-treated control mice demonstrated increased levels of periostin- and PCNA-positive cells, when compared with XAV-939–treated synovia. Additional sections from the same joint from the XAV-939–treated mouse were used as the isotype control. Images from the same joint region were used, although they are from separate sections. The H&E image is therefore reused. The representative isotype control shows minimal staining. Original magnification, ×20 (top row); ×80 (bottom 4 rows). (C) Proliferation was assessed by BrdU assay on synovial fibroblasts. Basal proliferation levels were significantly upregulated in OA patient fibroblasts compared with controls. Furthermore, WNT3A treatment of control fibroblasts also significantly upregulated proliferation. Wnt inhibition in OA fibroblasts decreased the proliferation rate. Two-way ANOVA with Tukey’s post-hoc test was performed, *P < 0.05, **P < 0.01, n = 6. For data presented as box-and-whiskers plots, horizontal lines indicate the medians, cross marks indicate the means, boxes indicate the 25th to 75th percentiles, and whiskers indicate the minimum and maximum values of the data set.

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