Activation of Nrf2 by sulfuretin stimulates chondrocyte differentiation and increases bone lengths in zebrafish
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Elongation of most bones occur at the growth plate throughendochondral ossification in postnatal mammals. The maturationof chondrocyte is a crucial factor in longitudinal bone growth,which is regulated by a complex network of paracrine and endocrinesignaling pathways. Here, we show that a phytochemicalsulfuretin can stimulate hypertrophic chondrocyte differentiationin vitro and in vivo. We found that sulfuretin stabilizednuclear factor (erythroid-derived 2)-like 2 (Nrf2), stimulatedits transcriptional activity, and induced expression of itstarget genes. Sulfuretin treatment resulted in an increase inbody length of zebrafish larvae and induced the expression ofchondrocyte markers. Consistently, a clinically available Nrf2activator, dimethyl fumarate (DMF), induced the expression ofhypertrophic chondrocyte markers and increased the body lengthof zebrafish. Importantly, we found that chondrocyte gene expressionin cell culture and skeletal growth in zebrafish stimulatedby sulfuretin were significantly abrogated by Nrf2 depletion,suggesting that such stimulatory effects of sulfuretin weredependent on Nrf2, at least in part. Taken together, these datashow that sulfuretin has a potential use as supporting ingredientsfor enhancing bone growth.
Abstract
Elongation of most bones occur at the growth plate throughendochondral ossification in postnatal mammals. The maturationof chondrocyte is a crucial factor in longitudinal bone growth,which is regulated by a complex network of paracrine and endocrinesignaling pathways. Here, we show that a phytochemicalsulfuretin can stimulate hypertrophic chondrocyte differentiationin vitro and in vivo. We found that sulfuretin stabilizednuclear factor (erythroid-derived 2)-like 2 (Nrf2), stimulatedits transcriptional activity, and induced expression of itstarget genes. Sulfuretin treatment resulted in an increase inbody length of zebrafish larvae and induced the expression ofchondrocyte markers. Consistently, a clinically available Nrf2activator, dimethyl fumarate (DMF), induced the expression ofhypertrophic chondrocyte markers and increased the body lengthof zebrafish. Importantly, we found that chondrocyte gene expressionin cell culture and skeletal growth in zebrafish stimulatedby sulfuretin were significantly abrogated by Nrf2 depletion,suggesting that such stimulatory effects of sulfuretin weredependent on Nrf2, at least in part. Taken together, these datashow that sulfuretin has a potential use as supporting ingredientsfor enhancing bone growth.
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