Premium
Inhibitory Regulation of Skin Fibrosis in Systemic Sclerosis by Apelin/APJ Signaling
Author(s) -
Yokoyama Yoko,
Sekiguchi Akiko,
Fujiwara Chisako,
Uchiyama Akihiko,
Uehara Akihito,
Ogino Sachiko,
Torii Ryoko,
Ishikawa Osamu,
Motegi Seiichiro
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40533
Subject(s) - apelin , fibrosis , medicine , endocrinology , cardiac fibrosis , in vivo , signal transduction , transforming growth factor , bleomycin , gene knockdown , chemistry , receptor , biology , microbiology and biotechnology , gene , biochemistry , chemotherapy
Objective Apelin/ APJ signaling has been determined to regulate cardiac and arterial fibrosis and to be involved in the pathogenesis of pulmonary arterial hypertension. Our objective was to elucidate the role of apelin in skin fibrosis in systemic sclerosis ( SS c). Methods Expression of apelin/ APJ in normal and SS c fibroblasts was compared. Effects of small interfering RNA depletion and the addition of apelin in fibroblasts were analyzed. The effect of apelin injections on bleomycin‐induced dermal fibrosis in mice was investigated. We analyzed the effects of the biased agonist of APJ , MM 07, on skin fibrosis in vitro and in vivo. Results The expression of apelin in SS c fibroblasts was significantly lower than that in normal fibroblasts. Serum apelin levels were negatively correlated with the modified Rodnan skin thickness score in SS c patients. Stimulation with transforming growth factor β1 ( TGF β1) inhibited apelin expression in fibroblasts, suggesting that activation of TGF β1 signaling in SS c might be responsible for reduced apelin expression in SS c fibroblasts. Small interfering RNA depletion of apelin from fibroblasts significantly enhanced fibrosis‐related gene expression, and treatment with apelin protein significantly inhibited TGF β1 signaling in fibroblasts. Administration of apelin significantly inhibited bleomycin‐induced dermal fibrosis in mice. We demonstrated that MM 07 had greater potential than apelin to inhibit fibrosis in vivo and in vitro. Conclusion Collectively, TGF β1 signaling and apelin signaling may counteract each other in the fibrotic process of SS c. Inhibitory regulation of TGF β1‐induced skin fibrosis by apelin/ APJ signaling may be involved in the pathogenesis of SS c and could be a therapeutic target for fibrosis in SS c patients.