Background/Purpose: Nuclear receptors are a family of transcription factors that is commonly targeted for therapeutic intervention. Dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome gene 1, DAX1, also known as NR0B1, has been shown to regulate fundamental cellular processes. However, its role in fibrotic diseases has not been investigated so far. Here, we aimed to characterize the role of DAX1 in the pathogenesis of SSc.

Methods: Expression of DAX1 was analyzed by Western blot, imaging mass cytometry (IMC) and immunofluorescence. The effects of DAX1 knockdown or DAX1 antagonist BPK-29 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). DAX1 signaling in TGFβ-stimulated fibroblasts was analyzed by RNASeq, co-immunoprecipitation and chromatin-immunoprecipitation.

Results: The expression of DAX1 was upregulated in SSc patients in a non-canonical TGFβ signaling dependent manner. DAX1 induced the activation of WNT/β-catenin signaling to drive fibroblast-to-myofibroblast transition. Knockout of DAX1 in murine skin by topical injection of DAX1-siRNA inhibited fibroblast-to-myofibroblast differentiation and ameliorated dermal fibrosis in two complementary mouse models of fibrosis. The selective DAX1 antagonist BPK-29 attenuated the TGFβ-induced myofibroblast activation or fibrotic tissue remodeling in cultured human dermal fibroblasts, and in three dimensional full-thickness skin equivalents. Moreover, inhibition of DAX1 ameliorated the expression of disease-relevant genes including WNT signaling in precision-cut slices of SSc skin. Mechanistically, DAX1 dimerized with E2F4 to promote WNT/β-catenin signaling via induction of WNT4 and WNT10B genes in cultured fibroblasts, in murine models of fibrosis and in precision-cut skin slices of SSc patients.

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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-nuclear-receptor-dax1-regulates-wnt-%ce%b2-catenin-signaling-to-promote-fibroblast-activation-and-skin-fibrosis-in-systemic-sclerosis/