Endoplasmic reticulum protein TXNDC5 modulates thyroid eye disease TGF-β1-induced myofibroblast transdifferentiation.

Autor:	Chiu HI; Ophthalmology, National Yang Ming Chiao Tung University - Yangming Campus, Taipei, Taiwan., Wu SB; Office of Business Development, Technology Commercialization Center, Taipei Medical University, Taipei, Taiwan., Wu AY; Ophthalmology, Stanford University School of Medicine, Palo Alto, California, USA., Tsai CC; Ophthalmology, National Yang Ming Chiao Tung University - Yangming Campus, Taipei, Taiwan cctsai@vghtpe.gov.tw.; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan.
Jazyk:	angličtina
Zdroj:	BMJ open ophthalmology [BMJ Open Ophthalmol] 2024 Dec 25; Vol. 9 (1). Date of Electronic Publication: 2024 Dec 25.
DOI:	10.1136/bmjophth-2024-001693
Abstrakt:	Aim: There remain limited therapies to treat thyroid eye disease (TED) orbital fibrosis, highlighting the urgency to develop novel targets. Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts are important pathogenetic factor of TED. Endoplasmic reticulum (ER) stress may play a role in TED pathogenesis since it has been linked to liver, kidney, heart and lung fibrotic remodelling. We would evaluate the role of thioredoxin domain containing 5 (TXNDC5), a fibroblast-enriched ER protein, in TGF-β1-induced myofibroblast transdifferentiation from TED orbital fibroblasts. Methods: Orbital fibroblasts from patients with TED were treated with TGF-β1 to investigate ER stress-relative gene expression especially for TXNDC5. To determine if TXNDC5 is involved in TGF-β1-induced fibrosis, we transfected TED orbital fibroblasts by lentivirus with a small hairpin RNA of pLKO-TXNDC5 gene (shTXNDC5) to knockdown TXNDC5 protein expression levels. After transfection of shTXNDC5 in TED orbital fibroblast followed by TGF-β1 treatment, we analysed TGF-β1-induced fibrosis protein expression. Results: We measured increased TXNDC5 gene and protein expression in primary TED orbital fibroblasts. TXNDC5 protein levels were increased in TED orbital fibroblasts under TGF-β1 stimulation (2.5, 5, 10 and 20 ng/mL). Moreover, TXNDC5 knockdown of attenuated TGFβ1 (5 ng/mL)-induced myofibroblast transdifferentiation and extracellular matrix protein upregulation whereas increasing TXNDC5 expression by a recombinant protein of TXNDC5 (rhTXNDC5) addition increased alpha smooth muscle actin, fibronectin and connective tissue growth factor protein expression. Conclusion: In conclusion, targeting TXNDC5 may be a novel therapeutic approach against TGF-β1-induced myofibroblast transdifferentiation in TED orbital fibroblasts. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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