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

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 deficiency. In addition to our previous finding of endoplasmic reticulum stress upon deficiency, we found calcium (Ca) overload jointly contributed to -associated chondrodysplasias. Continuous endoplasmic reticulum stress and cytosolic Ca 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 Ca overload. Our findings not only demonstrated the efficacy of melatonin in ameliorating abnormal function and cell fate of -deficient chondrocytes but also underscored its role in partially alleviating the skeletal dysplasia seen in ; mice. As revealed by histology and micro-CT analyses, melatonin significantly improved retarded cartilage growth, defective trabecular bone formation, and tibial genu varum . Collectively, these data shed translational insights for drug development and support melatonin as a potential treatment for -related chondrodysplasias.