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This galley proof is being listed electronically before publishing the final manuscript (It's not final version).

Activation of Nrf2 by sulfuretin stimulates chondrocyte differentiation and increases bone lengths in zebrafish
Seo-Hyuk Chang1,# ( Research worker), Hoi-Khoanh Giong2,# ( Research worker), Da-Young Kim1 (Graduate student), Suji Kim1 ( Research worker), Seungjun Oh1 (Graduate student), Ui Jeong Yun4 (Professor), Jeong- Soo Lee2,3,5,# (Professor), Kye Won Park 1,*,# (Professor)
1Department of Food Science and Biotechnology, Sungkyunkwan University,
2Microbiome Convergence Research center, KRIBB,
3KRIBB School, University of Science and Technology,
4Department of Chemical and Biological Engineering,School of Living and Environmental engineering, Dongyang Mirae University,
5Sungkyunkwan University School of Medicine, Sungkyunkwan University
Elongation of most bones occur at the growth plate through endochondral ossification in postnatal mammals. The maturation of chondrocyte is a crucial factor in longitudinal bone growth, which is regulated by a complex network of paracrine and endocrine signaling pathways. Here, we show that a phytochemical sulfuretin can stimulate hypertrophic chondrocyte differentiation in vitro and in vivo. We found that sulfuretin stabilized nuclear factor (erythroid-derived 2)-like 2 (Nrf2), stimulated its transcriptional activity, and induced expression of its target genes. Sulfuretin treatment resulted in an increase in body length of zebrafish larvae and induced the expression of chondrocyte markers. Consistently, a clinically available Nrf2 activator, dimethyl fumarate (DMF), induced the expression of hypertrophic chondrocyte markers and increased the body length of zebrafish. Importantly, we found that chondrocyte gene expression in cell culture and skeletal growth in zebrafish stimulated by sulfuretin were significantly abrogated by Nrf2 depletion, suggesting that such stimulatory effects of sulfuretin were dependent on Nrf2, at least in part. Taken together, these data show that sulfuretin has a potential use as supporting ingredients for enhancing bone growth.
Abstract, Accepted Manuscript(in press) [Submitted on April 14, 2023, Accepted on May 22, 2023]
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