Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis
Caressa Lietman, … , Mohit Kapoor, Pampee P. Young
Caressa Lietman, … , Mohit Kapoor, Pampee P. Young
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e96308. https://doi.org/10.1172/jci.insight.96308.
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Research Article Aging Inflammation

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

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 1

Wnt signaling is upregulated in the joint after injury.

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Wnt signaling is upregulated in the joint after injury. (A) Ten-week-old...
(A) Ten-week-old male mice were subjected to destabilization of the medial meniscus (DMM) surgery. Three weeks after injury, they were injected intra-articularly with saline or Wnt inhibitor every 10 days for a total of 5 times, and knee joints were collected 10 weeks after surgery. (B and C) Synovial tissue was stained by immunofluorescence for β-catenin (red) and periostin (POSTN) (green), a marker of fibroblasts. DAPI (blue) was used as a counterstain, and yellow indicates costaining of Wnt activation in fibroblasts. (B) Uninjured joints and joints after DMM surgery show upregulation of Wnt/β-catenin signaling after injury and increased periostin-positive cells in the synovium. (C) Saline-treated controls, compared with XAV-939–treated joints, indicate that treatment abrogated Wnt/β-catenin signaling in synovial fibroblasts. (D) Additional sections from the same joint from after DMM surgery 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 from B. The representative isotype control shows no significant staining. Original magnification, ×40 (top rows); ×80 (bottom rows).