Date Published: March 14, 2019
Publisher: Public Library of Science
Author(s): Ching-Ying Wu, Wen-Li Hsu, Ming-Hsien Tsai, Chee-Yin Chai, Chia-Jung Yen, Chu-Huang Chen, Jian-He Lu, Hsin-Su Yu, Tohru Yoshioka, Etsuro Ito.
Transforming growth factor-β (TGF-β) is an important target for treating systemic sclerosis (SSc). However, our study revealed three levels of TGF-β1 expression in SSc patients, indicating that inhibiting TGF-β is not sufficient to treat SSc. A previous clinical trial also displayed disappointing results. Thus, our study attempted to search for a potential novel approach. Ingenuity Pathway Analysis (IPA) indicated that the SSc pathological pathways were closely associated with store-operated Ca2+ entry (SOCE)-regulated signals, and SOCE activity was found to be increased in SSc fibroblasts. Further treatment of SSc fibroblasts with SOCE inhibitors, 2APB, and associated calcium channel inhibitors SKF96365, and indomethacin, showed that the SOCE inhibitors selectively decreased fibrosis markers and altered the cell morphology. Consequently, SOCE inhibitors, especially 2APB and indomethacin, caused the dedifferentiation of SSc fibroblasts via cytoskeleton remodeling and altered collagen secretion and restored the cell mobility. We further explained SSc pathogenesis as fibroblast differentiation with SOCE. Treatment with exogenous factors, gelatin-1, FAM20A and human albumin, which were identified from the conditioned medium of SSc fibroblasts, was important for regulating the differentiation of fibroblasts with higher levels of SOCE and α-SMA. Conclusively, to treat SSc, blockage of the increased SOCE activity in SSc induces the dedifferentiation of SSc fibroblasts and simultaneously changes the extracellular matrix (ECM) structure to limit SSc pathogenesis.
Systemic sclerosis (SSc), a severe multisystem autoimmune disease, is characterized by progressive fibrosis that can influence all organs in the body . Previous study indicated the majority of SSc deaths involve pulmonary fibrosis, pulmonary arterial hypertension and cardiac causes .However, the low efficacy of immunosuppressive treatments suggest a complicated pathogenesis of fibrosis and unknown mechanisms in SSc. For treating fibrotic diseases, especially SSc, several recent studies focused on transforming growth factor-β (TGF-β) as a potential target for anti-fibrotic therapy because TGF-β is a crucial mediator of fibrosis.
In this study we attempted to look for a potential novel approach that would be effective for SSc therapy. Although TGF-β1 is a crucial target in treating SSc, skin biopsies from SSc patients revealed that the TGF-β1 level differed from that of the paired normal skin biopsies. Consequently, based on IPA analysis, we suggested that SOCE inhibitors efficiently attenuated SSc pathogenesis, inducing the dedifferentiation of SSc fibroblasts by cytoskeleton remodeling and changes in collagen secretion. The cytoskeleton remodeling in SSc fibroblasts was due to selective inhibition of cytoskeleton components by SOCE inhibitors; the changes in collagen secretion contributed to disruption of the ECM structure and affected the microenvironmental signals applied to the cells. The microenvironment is the major factor resulting in SSc pathogenesis, and treatment with extracellular factors, such as human albumin, caused fibroblast differentiation. Thus, to treat SSc, endogenous blockage of excess Ca2+ signals and exogenous disruption of the ECM structure have potential as novel approaches.