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Background: Nuclear receptors are a family of transcription factors that is commonly targeted for therapeutic intervention in different diseases. Dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome gene 1, DAX1, also known as NR0B1, is a less well characterized orphan nuclear receptor that has been implicated in the development of hormone-responsive tissues. However, its role in fibrotic diseases has not been investigated so far. Objectives: The aim of the present study was to characterize the role of DAX1 in the pathogenesis of fibrotic tissue remodeling in SSc. Methods: Expression of DAX1 was analyzed by Western blot and immunofluorescence. The effects of DAX1 knockdown or treatment with the selective DAX1 antagonist BPK29 on collagen production and myofibroblast differentiation were analyzed in cultured human fibroblasts, in bleomycin- and cGvHD-induced dermal fibrosis in mice, human 3D full-thickness skin equivalents and precision-cut human skin slices (PCSS). RNA sequencing was performed in TGFβ-stimulated fibroblasts transfected with DAX1 siRNA or non-targeting siRNA. Results: The expression of DAX1 is upregulated in the skin of SSc patients in a TGFβ/JNK or TGFβ/ERK dependent manner. Inactivation of DAX1 by siRNA or by pharmaceutical inhibition ameliorated fibroblast-to-myofibroblast transition and collagen release in cultured human dermal fibroblasts, in human full-thickness skin equivalents and the skin of mice with bleomycin- or cGvHD-induced dermal fibrosis. Mechanistically, DAX1 promoted activation of WNT/β-catenin signaling to drive fibroblast activation. Inhibition of DAX1 also reduced the expression of disease-relevant genes including WNT/β-catenin signaling in precision-cut slices of SSc skin. Conclusion: DAX1 is upregulated in SSc in a TGFβ-dependent manner to promote fibroblast activation via WNT/β-catenin signaling. Inactivation of DAX1 normalizes WNT/β-catenin signaling, inhibits fibroblast-to-myofibroblast transition and ameliorates experimental fibrosis. Targeting of DAX1 may thus offer potential for therapeutic intervention. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Lichong Shen: None declared, Yun Zhang: None declared, Andrea-Hermina Györfi: None declared, Yi-nan Li: None declared, Alexandru-Emil Matei: None declared, Xuezhi Hong: None declared, Minrui Liang: None declared, Honglin Zhu: None declared, Jörg Distler JHWD is stock owner of 4D Science and Scientific lead of FibroCure, JHWD has consultancy relationships with Actelion, Active Biotech, AnaMar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, MSD, Pfizer, Roche/Genetech/Chugai and UCB, JHWD has received research funding from AbbVie, AnaMar, Active Biotech, AstraZeneca, Argenx, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Lilly, Novartis, Sanofi-Aventis, RedX, UCB.
Shen et al. (Sat,) studied this question.