Highlights
- •2-APB induces dedifferentiation in TGF-β1-induced myofibroblasts.
- •Inhibition of intracellular Ca2+ regulation by 2-APB restrains the expression of fibrotic markers through inhibiting TGF-β1/SMAD3 signaling.
- •Treatment with 2-APB in the bleomycin-induced SSc mice alleviates SSc pathogenesis.
- •2-APB is a potential candidate for treating fibrotic diseases.
Abstract
Background
Systemic sclerosis (SSc) causes progressive fibrosis of multiple organs with the low
efficacy of immunosuppressive therapies. Our previous study indicated the SSc pathological
pathways are closely correlated with Ca2+ signals, and blockage of the intracellular Ca2+ elevation facilitates inhibition of SSc pathogenesis.
Objective
Transforming growth factor β (TGF-β)-modulated SMAD signaling is crucial in regulating
SSc pathogenesis. Whether Ca2+ signals are involved in TGF-β1/SMAD signaling-induced fibrotic process has been further
investigated.
Methods
We utilized TGF-β1-induced myofibroblasts as a model to detect how Ca2+ signals affected SSc pathogenesis, and investigated the combination of treatment
with store-operated Ca2+ entry (SOCE) associated inhibitors, 2-aminoethyl diphenylborinate (2-APB) and SKF96365
to restrain the increased Ca2+ signaling in myofibroblasts. In addition, the SSc bleomycin mouse model was used
to detect the effect of 2-APB on SSc pathogenesis in vivo.
Results
Our findings revealed increased levels of TGF-β1 production in SSc was associated
with intracellular Ca2+ activity, and inhibition of intracellular Ca2+ regulation by 2-APB resulted in the dedifferentiation of TGF-β1-induced myofibroblasts.
This was due to the fact that 2-APB restrained the expression fibrotic markers, α-SMA,
fibronectin and vimentin through inhibiting TGF-β1/SMAD3 signaling. Thus, subcutaneous
injection of 2-APB improved bleomycin-induced skin and pulmonary fibrosis.
Conclusion
2-APB is a potential candidate for treating fibrosis, by disrupting intracellular
Ca2+ regulation in SSc to induce the dedifferentiation of myofibroblasts and meliorates
fibrosis pathogenesis via inhibiting TGF-β1/SMAD3 signaling.
Keywords
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Article info
Publication history
Published online: July 12, 2021
Accepted:
July 10,
2021
Received in revised form:
July 6,
2021
Received:
January 22,
2021
Identification
Copyright
© 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
