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Full Length Article | Open Access

Melatonin ameliorates Slc26a2-associated chondrodysplasias by attenuating endoplasmic reticulum stress and apoptosis of chondrocytes

Pan Lia,1, Chao Zhenga,1, Jingyan Hua,1, Weiguang Lua, Dong Wanga, Xue Haob, Chengxiang Zhaoa, Liu Yanga( ), Zhuojing Luoa( ), Qiang Jieb,c,d( )
Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
Pediatric Orthopaedic Hospital, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710032, China
Research Center for Skeletal Developmental Deformity and Injury Repair, College of Life Sciences and Medicine, Northwestern University, Xi'an, Shaanxi 710032, China
Xi'an Key Laboratory of Skeletal Development Deformity and Injury Repair, Xi'an, Shaanxi 710032, China

1 These authors contributed equally to this work.

Peer review under responsibility of Chongqing Medical University.

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Abstract

Although the pathogenesis and mechanism of congenital skeletal dysplasia are better understood, progress in drug development and intervention research remains limited. Here we report that melatonin treatment elicits a mitigating effect on skeletal abnormalities caused by SLC26A2 deficiency. In addition to our previous finding of endoplasmic reticulum stress upon SLC26A2 deficiency, we found calcium (Ca2+) overload jointly contributed to SLC26A2-associated chondrodysplasias. Continuous endoplasmic reticulum stress and cytosolic Ca2+ overload in turn triggered apoptosis of growth plate chondrocytes. Melatonin, known for its anti-oxidant and anti-inflammatory properties, emerged as a promising therapeutic approach in our study, which enhanced survival, proliferation, and maturation of chondrocytes by attenuating endoplasmic reticulum stress and Ca2+ overload. Our findings not only demonstrated the efficacy of melatonin in ameliorating abnormal function and cell fate of SLC26A2-deficient chondrocytes in vitro but also underscored its role in partially alleviating the skeletal dysplasia seen in Col2a1-CreERT2; Slc26a2fl/fl mice. As revealed by histology and micro-CT analyses, melatonin significantly improved retarded cartilage growth, defective trabecular bone formation, and tibial genu varum in vivo. Collectively, these data shed translational insights for drug development and support melatonin as a potential treatment for SLC26A2-related chondrodysplasias.

Keywords

Ca2+overloadChondrodysplasiaEndoplasmic reticulum stressMelatoninSLC26A2

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Genes & Diseases
Volume 12 Issue 2,
March 2025
Article number: 101350
DOI: 10.1016/j.gendis.2024.101350
Cite this article:
Li P, Zheng C, Hu J, et al. Melatonin ameliorates Slc26a2-associated chondrodysplasias by attenuating endoplasmic reticulum stress and apoptosis of chondrocytes. Genes & Diseases, 2025, 12(2): 101350. https://doi.org/10.1016/j.gendis.2024.101350

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Received: 20 January 2024
Accepted: 11 April 2024
Published: 14 June 2024
© 2024 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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