Arthritis & rheumatology (Hoboken, N.J.) · 2026
The Nuclear Receptor Testicular Receptor 4 Orchestrates Cytoskeletal Organization in a G Protein Subunit Alpha 12/Rho-Associated Protein Kinase-Dependent Manner to Promote Myofibroblast Differentiation and Tissue Fibrosis in Systemic Sclerosis.
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Zhang Yun, Shen Lichong, Zheng Junhui, Baur Gisela, Yasen Dilidaer, Zhu Honglin, Li Yi-Nan, Meng Xianyi, Trinh-Minh Thuong, Filla Tim, Chakraborty Debomita, Györfi Andrea-Hermina, Bergmann Christina, Reich Adam, Kreuter Alexander, Schett Georg, Distler Jörg H W
Аннотация
OBJECTIVE: Members of the superfamily of nuclear receptors have been implicated in inflammatory processes and pathologic tissue remodeling and have emerged as attractive targets for pharmaceutical intervention. However, the role of testicular receptor 4 (TR4; or Nr2c2) in fibroblast activation and rheumatologic diseases has not yet been investigated.
METHODS: TR4 expression in human skin and experimental fibrosis were determined by immunofluorescence staining and Western blot. RNA sequencing (RNAseq) was performed in transforming growth factor β (TGFβ)-stimulated fibroblasts with or without TR4 knockdown by small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin and extracellular matrix staining, and Rho-associated protein kinase (ROCK) activity was assessed by enzyme-linked immunosorbent assay. Fibroblast-specific Tr4 knockout mice were subjected to constitutively active TGFβ receptor type I-, bleomycin-, and chronic graft-versus-host disease-induced dermal fibrosis and bleomycin-induced pulmonary fibrosis. Precision-cut skin slices (PCSSs) from patients with systemic sclerosis (SSc) were used for TR4 knockdown studies.
RESULTS: TR4 was up-regulated in fibroblasts in the skin of patients with SSc and in murine models of SSc. TGFβ induced TR4 in fibroblasts in an SMAD3-dependent manner. Knockdown of TR4 prevented fibroblast-to-myofibroblast transition, and fibroblast-specific knockout of Tr4 ameliorated experimental murine skin and pulmonary fibrosis. RNAseq and functional experiments identified the profibrotic effects of TR4 were dependent on G protein subunit alpha 12- and ROCK-associated cytoskeletal remodeling. PCSSs confirmed that TR4 regulates ROCK signaling and the expression of profibrotic genes in SSc skin.
CONCLUSION: TR4 is up-regulated in SSc in a TGFβ-dependent manner and drives fibroblast activation. Inhibition of TR4 prevents ROCK activation and fibroblast-to-myofibroblast transition and ameliorates dermal and pulmonary fibrosis, highlighting TR4 as a potential therapeutic target in SSc and related diseases.
METHODS: TR4 expression in human skin and experimental fibrosis were determined by immunofluorescence staining and Western blot. RNA sequencing (RNAseq) was performed in transforming growth factor β (TGFβ)-stimulated fibroblasts with or without TR4 knockdown by small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin and extracellular matrix staining, and Rho-associated protein kinase (ROCK) activity was assessed by enzyme-linked immunosorbent assay. Fibroblast-specific Tr4 knockout mice were subjected to constitutively active TGFβ receptor type I-, bleomycin-, and chronic graft-versus-host disease-induced dermal fibrosis and bleomycin-induced pulmonary fibrosis. Precision-cut skin slices (PCSSs) from patients with systemic sclerosis (SSc) were used for TR4 knockdown studies.
RESULTS: TR4 was up-regulated in fibroblasts in the skin of patients with SSc and in murine models of SSc. TGFβ induced TR4 in fibroblasts in an SMAD3-dependent manner. Knockdown of TR4 prevented fibroblast-to-myofibroblast transition, and fibroblast-specific knockout of Tr4 ameliorated experimental murine skin and pulmonary fibrosis. RNAseq and functional experiments identified the profibrotic effects of TR4 were dependent on G protein subunit alpha 12- and ROCK-associated cytoskeletal remodeling. PCSSs confirmed that TR4 regulates ROCK signaling and the expression of profibrotic genes in SSc skin.
CONCLUSION: TR4 is up-regulated in SSc in a TGFβ-dependent manner and drives fibroblast activation. Inhibition of TR4 prevents ROCK activation and fibroblast-to-myofibroblast transition and ameliorates dermal and pulmonary fibrosis, highlighting TR4 as a potential therapeutic target in SSc and related diseases.