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

作　　者：Pan Li Chao Zheng Jingyan Hu Weiguang Lu Dong Wang Xue Hao Chengxiang Zhao Liu Yang Zhuojing Luo Qiang Jie 

机构地区：[1]Institute of Orthopedic Surgery,Xijing Hospital,Fourth Military Medical University,Xi'an,Shaanxi 710032,China [2]Pediatric Orthopaedic Hospital,Honghui Hospital,Xi'an Jiaotong University,Xi'an,Shaanxi 710032,China [3]Research Center for Skeletal Developmental Deformity and Injury Repair,College of Life Sciences and Medicine,Northwestern University,Xi'an,Shaanxi 710032,China [4]Xi'an Key Laboratory of Skeletal Development Deformity and Injury Repair,Xi'an,Shaanxi 710032,China

出　　处：《Genes & Diseases》2025年第2期425-437,共13页基因与疾病(英文)

基　　金：supported by the National Natural Science Foundation of China (No.82272442,82372361);the Key Industrial Chain Program of Shaanxi,China (No.2022ZDLSF02-12).

摘　　要：Although the pathogenesis and mechanism of congenital skeletal dysplasia are bet-ter 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(Ca^(2+))overload jointly contributed to SLC26A2-associ-ated chondrodysplasias.Continuous endoplasmic reticulum stress and cytosolic Ca^(2+)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 endo-plasmic reticulum stress and Ca^(2+)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;slc26a2f/n 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.

关 键 词：Ca^(2+)overload CHONDRODYSPLASIA Endoplasmic reticulum stress MELATONIN SLC26A2 

分 类 号：R73[医药卫生—肿瘤]