- •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.
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.
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.
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.
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.
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.
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Published online: July 12, 2021
Accepted: July 10, 2021
Received in revised form: July 6, 2021
Received: January 22, 2021
© 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.