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

• Published in: Genes & diseases Vol. 12; no. 2; p. 101350
• Main Authors: Li, Pan, Zheng, Chao, Hu, Jingyan, Lu, Weiguang, Wang, Dong, Hao, Xue, Zhao, Chengxiang, Yang, Liu, Luo, Zhuojing, Jie, Qiang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2025; KeAi Communications Co., Ltd
• Subjects: Ca2+overload; Chondrodysplasia; Endoplasmic reticulum stress; Melatonin; SLC26A2; Ca2+overload; Melatonin; SLC26A2; Chondrodysplasia; Endoplasmic reticulum stress
• ISSN: 2352-3042; 2352-3042
• DOI: 10.1016/j.gendis.2024.101350

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.