Induction of Canonical Wnt Signaling by Synovial Overexpression of Selected Wnts Leads to Protease Activity and Early Osteoarthritis-Like Cartilage Damage

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Induction of Canonical Wnt Signaling by Synovial Overexpression of Selected Wnts Leads to Protease Activity and Early Osteoarthritis-Like Cartilage Damage Martijn H. van den Bosch, Arjen B. Blom, Annet W. Sloetjes, Marije I. Koenders, Fons A. van de Loo, Wim B. van den Berg, Peter L. van Lent, Peter M. van der Kraan The American Journal of Pathology Volume 185, Issue 7, Pages 1970-1980 (July 2015) DOI: 10.1016/j.ajpath.2015.03.013 Copyright © 2015 American Society for Investigative Pathology Terms and Conditions

Figure 1 Adenoviral targeting resulted in increased expression of Wnt5a, Wnt8a, and Wnt16. A: Quantitative real-time PCR showed that targeting of primary murine synovial fibroblasts with adenoviral vectors containing Wnt5a, Wnt8a, and Wnt16 results in increased expression of these Wnts at the RNA level, 24 hours after overexpression. B: Western blot showed increased protein expression. C: Intra-articular injection of adenoviral vectors containing Wnt5a, Wnt8a, and Wnt16 into murine knee joints resulted in increased expression of these members of the Wnt signaling pathway in the synovium 3 days after overexpression. D: In vivo overexpression with the adenoviral vectors resulted in increased expression specifically in the synovium, but not in the cartilage. Representative Western blots and a representative image of an X-Gal staining are shown. Values are presented as −dCT means ± SEM, indicated by the error bars. C, cartilage; ND, not detectable; P, patella; S, synovium; T, tibia. The American Journal of Pathology 2015 185, 1970-1980DOI: (10.1016/j.ajpath.2015.03.013) Copyright © 2015 American Society for Investigative Pathology Terms and Conditions

Figure 2 Synovial overexpression of Wnt8a and Wnt16, but not Wnt5a, resulted in the accumulation of β-catenin. A: Immunohistochemical staining for β-catenin showed that adenoviral overexpression of Wnt8a and Wnt16 results in increased staining in the cartilage 7 days after overexpression. By contrast, overexpression of Wnt5a had no effect. B: Quantitative real-time PCR showed that accumulation of β-catenin after overexpression of Wnt8a and Wnt16 results in increased expression of Axin2 in the cartilage. By contrast, overexpression of Wnt5a had no effect. Representative images of β-catenin staining are shown. Values are presented as −dCT means ± SEM. ∗P < 0.05 versus control. The American Journal of Pathology 2015 185, 1970-1980DOI: (10.1016/j.ajpath.2015.03.013) Copyright © 2015 American Society for Investigative Pathology Terms and Conditions

Figure 3 Synovial overexpression of Wnts that results in canonical signaling increased cartilage damage. A: Histological staining with Safranin O and Fast Green showed that synovial overexpression of Wnt8a and Wnt16, but not Wnt5a, results in superficial erosive cartilage lesions, mainly found at the medial tibia near the cruciate ligaments at day 7 after overexpression. B: Scoring of the cartilage damage using the Pritzker scoring system, modified for mouse, showed that canonical Wnt signaling induced by Wnt8a and Wnt16 significantly increases cartilage damage at the medial tibia and at all four cartilage areas in the tibiofemoral joint, whereas noncanonical Wnt signaling by Wnt5a overexpression did not increase the cartilage damage. Representative histological images are shown. Cartilage damage is presented as mean histological osteoarthritis scores ± SEM. ∗P < 0.05, ∗∗P < 0.01 versus control. The American Journal of Pathology 2015 185, 1970-1980DOI: (10.1016/j.ajpath.2015.03.013) Copyright © 2015 American Society for Investigative Pathology Terms and Conditions

Figure 4 Osteoarthritis-like cartilage pathologies resulted from protease activity. A: Immunohistochemical staining for the aggrecanase neoepitope NITEGE and the matrix metalloproteinase (MMP) neoepitope VDIPEN showed that the superficial erosive cartilage lesions induced by the overexpression of Wnt8a and Wnt16 are associated with strong NITEGE staining, whereas there was only a minor increase in VDIPEN. B: In addition to the superficial erosive cartilage lesions, several other types of pathologies in the cartilage after overexpression of Wnt8a or Wnt16, resulting in canonical signaling, were observed. Staining for NITEGE and VDIPEN showed that profound superficial proteoglycan depletion is associated with both aggrecanase and MMP activity. In addition, tears in the cartilage were associated mainly with MMP activity as measured by VDIPEN staining. Representative images of all staining are shown after overexpression of Wnt8a or Wnt16. SafO, Safranin O. The American Journal of Pathology 2015 185, 1970-1980DOI: (10.1016/j.ajpath.2015.03.013) Copyright © 2015 American Society for Investigative Pathology Terms and Conditions

Figure 5 Inhibition of canonical Wnt signaling by Dickkopf-1 (DKK-1) overexpression reduced the cartilage damage. A: Histological staining with Safranin O and Fast Green showed that synovial overexpression of DKK-1 reduces the superficial erosive cartilage lesions induced by canonical Wnt signaling at day 7 after overexpression. B: Scoring of the cartilage damage using the Pritzker scoring system, modified for mouse, showed that inhibition of canonical Wnt signaling by overexpression of the selective inhibitor DKK-1 significantly reduces the cartilage damage induced by canonical Wnt signaling in the tibiofemoral joint. Representative histological images are shown. Cartilage damage is presented as mean histological osteoarthritis scores ± SEM. ∗P < 0.05 versus control. The American Journal of Pathology 2015 185, 1970-1980DOI: (10.1016/j.ajpath.2015.03.013) Copyright © 2015 American Society for Investigative Pathology Terms and Conditions

Figure 6 WISP1, a downstream protein of canonical Wnt signaling, might be partially responsible for the osteoarthritis-like cartilage pathology. A–C: WISP1 was successfully overexpressed with an adenoviral vector both in vitro in murine synovial fibroblasts (A and C) and in vivo in synovial tissue (B). D and E: An increased incidence of superficial erosive cartilage lesions at the medial tibia after overexpression of WISP1 (D) leads to significantly increased cartilage damage (E). F: The lesions are associated with increased NITEGE staining, whereas VDIPEN staining is only increased to a minor extent. Representative Western blots and images are shown. Gene expression is presented as −dCT means ± SEM. Cartilage damage is presented as mean histological osteoarthritis scores ± SEM. ∗∗P < 0.01 versus control. The American Journal of Pathology 2015 185, 1970-1980DOI: (10.1016/j.ajpath.2015.03.013) Copyright © 2015 American Society for Investigative Pathology Terms and Conditions