Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone
Abstract Background Both loss- and gain-of-function of Wnt/β-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/β-catenin signaling in the superficial zone (SFZ) of articular cartilage. Methods Wnt/β-catenin signaling acti...
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2019-11-01
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Online Access: | http://link.springer.com/article/10.1186/s13075-019-2041-5 |
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doaj-e2aa9cb1efc747c8a4b1193e7c631b852020-11-24T21:56:04ZengBMCArthritis Research & Therapy1478-63622019-11-0121111110.1186/s13075-019-2041-5Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zoneFengjun Xuan0Fumiko Yano1Daisuke Mori2Ryota Chijimatsu3Yuji Maenohara4Hideki Nakamoto5Yoshifumi Mori6Yuma Makii7Takeshi Oichi8Makoto Mark Taketo9Hironori Hojo10Shinsuke Ohba11Ung-il Chung12Sakae Tanaka13Taku Saito14Sensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoBone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of TokyoBone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoDivision of Experimental Therapeutics, Graduate School of Medicine, Kyoto UniversityCenter for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of TokyoCenter for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of TokyoCenter for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoSensory & Motor System Medicine, Graduate School of Medicine, The University of TokyoAbstract Background Both loss- and gain-of-function of Wnt/β-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/β-catenin signaling in the superficial zone (SFZ) of articular cartilage. Methods Wnt/β-catenin signaling activity was analyzed using TOPGAL mice. We generated Prg4-Cre ERT2 ;Ctnnb1 fl/fl and Prg4-Cre ERT2 ;Ctnnb1-ex3 fl/wt mice for loss- and gain-of-function, respectively, of Wnt/β-catenin signaling in the SFZ. Regulation of Prg4 expression by Wnt/β-catenin signaling was examined in vitro, as were upstream and downstream factors of Wnt/β-catenin signaling in SFZ cells. Results Wnt/β-catenin signaling activity, as determined by the TOPGAL reporter, was high specifically in the SFZ of mouse adult articular cartilage, where Prg4 is abundantly expressed. In SFZ-specific β-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific β-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by β-catenin knockout, while it was upregulated by β-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/β-catenin signaling activation increased mRNA levels of Creb1, a potent transcription factor for Prg4. Conclusions We demonstrated that Wnt/β-catenin signaling regulates Prg4 expression in the SFZ of mouse adult articular cartilage, which plays essential roles in the homeostasis of articular cartilage.http://link.springer.com/article/10.1186/s13075-019-2041-5OsteoarthritisChondrocyteSuperficial zoneWnt signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fengjun Xuan Fumiko Yano Daisuke Mori Ryota Chijimatsu Yuji Maenohara Hideki Nakamoto Yoshifumi Mori Yuma Makii Takeshi Oichi Makoto Mark Taketo Hironori Hojo Shinsuke Ohba Ung-il Chung Sakae Tanaka Taku Saito |
spellingShingle |
Fengjun Xuan Fumiko Yano Daisuke Mori Ryota Chijimatsu Yuji Maenohara Hideki Nakamoto Yoshifumi Mori Yuma Makii Takeshi Oichi Makoto Mark Taketo Hironori Hojo Shinsuke Ohba Ung-il Chung Sakae Tanaka Taku Saito Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone Arthritis Research & Therapy Osteoarthritis Chondrocyte Superficial zone Wnt signaling |
author_facet |
Fengjun Xuan Fumiko Yano Daisuke Mori Ryota Chijimatsu Yuji Maenohara Hideki Nakamoto Yoshifumi Mori Yuma Makii Takeshi Oichi Makoto Mark Taketo Hironori Hojo Shinsuke Ohba Ung-il Chung Sakae Tanaka Taku Saito |
author_sort |
Fengjun Xuan |
title |
Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone |
title_short |
Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone |
title_full |
Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone |
title_fullStr |
Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone |
title_full_unstemmed |
Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone |
title_sort |
wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone |
publisher |
BMC |
series |
Arthritis Research & Therapy |
issn |
1478-6362 |
publishDate |
2019-11-01 |
description |
Abstract Background Both loss- and gain-of-function of Wnt/β-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/β-catenin signaling in the superficial zone (SFZ) of articular cartilage. Methods Wnt/β-catenin signaling activity was analyzed using TOPGAL mice. We generated Prg4-Cre ERT2 ;Ctnnb1 fl/fl and Prg4-Cre ERT2 ;Ctnnb1-ex3 fl/wt mice for loss- and gain-of-function, respectively, of Wnt/β-catenin signaling in the SFZ. Regulation of Prg4 expression by Wnt/β-catenin signaling was examined in vitro, as were upstream and downstream factors of Wnt/β-catenin signaling in SFZ cells. Results Wnt/β-catenin signaling activity, as determined by the TOPGAL reporter, was high specifically in the SFZ of mouse adult articular cartilage, where Prg4 is abundantly expressed. In SFZ-specific β-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific β-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by β-catenin knockout, while it was upregulated by β-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/β-catenin signaling activation increased mRNA levels of Creb1, a potent transcription factor for Prg4. Conclusions We demonstrated that Wnt/β-catenin signaling regulates Prg4 expression in the SFZ of mouse adult articular cartilage, which plays essential roles in the homeostasis of articular cartilage. |
topic |
Osteoarthritis Chondrocyte Superficial zone Wnt signaling |
url |
http://link.springer.com/article/10.1186/s13075-019-2041-5 |
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