Role of TGF Signaling in Maternal Ethanol-Induced Fetal Articular Cartilage Dysplasia and Adult Onset of Osteoarthritis in Male Rats
Role of TGF Signaling in Maternal Ethanol-Induced Fetal Articular Cartilage Dysplasia and Adult Onset of Osteoarthritis in Male Rats
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DOI：
10.1093/toxsci/kfy080
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发表时间：
2018-07
影响因子：
3.8
通讯作者：
Qubo Ni;Kaihang Lu;Jing Li;Yang Tan;Jun Qin;J. Magdalou;Liaobin Chen;Hui Wang
中科院分区：
文献类型：
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作者：
Qubo Ni;Kaihang Lu;Jing Li;Yang Tan;Jun Qin;J. Magdalou;Liaobin Chen;Hui Wang
基于我们之前的研究结果，即后代产前乙醇暴露增加了成人骨关节炎的易感性，本研究旨在进一步研究乙醇对胎儿关节软骨发育的直接毒性。将大鼠骨髓来源的基质细胞封装在藻酸盐珠中，在软骨形成分化培养基中孵育，并用浓度为 0、4、20 和 100 mM 的乙醇处理培养 4 周。妊娠大鼠从妊娠第9～20天开始给予乙醇（4 g/kg/天）治疗。在妊娠第20周和生后第2、6、12周处死8只雄性子代，每组8只8周龄雄性子代大鼠，关节内注射或不注射木瓜蛋白酶治疗4周，以验证成年骨关节炎的易感性。乙醇处理导致骨髓基质细胞向软骨细胞的分化不良，并抑制转化生长因子-β (TGFβ)-smad2/3-Sox9 信号通路的表达。动物实验中，乙醇治疗组关节软骨形态较对照组更紊乱，基质不深，软骨较薄，软骨发育较差。乙醇治疗组的 TGFβ 信号通路在所有时间点都持续较低。关节内注射木瓜蛋白酶后，组织学分析和Mankin评分显示乙醇治疗组软骨破坏增加。乙醇会导致关节软骨发育不良，这种发育不良是在成年后通过功能低下的 TGFβ 信号通路进行编程的，并且这种关节软骨对外部刺激的耐受性显着降低。
Based on our previous findings that prenatal ethanol exposure in offspring increased susceptibility to adult osteoarthritis, this study aimed to further investigate the direct toxicity of ethanol on fetal articular cartilage development. Rat bone marrow-derived stroma cells were capsulated in alginate beads, incubated in a chondrogenic differentiation medium, and cultured for 4 weeks with ethanol treatment at concentrations of 0, 4, 20, and 100 mM. Pregnant rats were treated with ethanol (4 g/kg/day) from gestational days (GDs) 9 to 20. At GD20 and postnatal weeks 2, 6, and 12, 8 male offspring were sacrificed, and 8 male offspring rats of 8-weeks old in each group were treated with or without intraarticular injection of papain for 4 weeks to verify the susceptibility of adult osteoarthritis. Ethanol treatment resulted in poor differentiation of bone marrow-derived stroma cells to chondrocytes and suppressed the expression of the transforming growth factor-β (TGFβ)-smad2/3-Sox9 signaling pathway. In animal experiments, the shape of articular cartilage in the ethanol treatment group was more disordered than that of the control group, the matrix was not deep, and the cartilage was thin, which showed poor cartilage development. The TGFβ signaling pathway in the ethanol treatment group was persistently low at all time points. After intraarticular injection of papain, histological analyses, and the Mankin score revealed increased cartilage destruction in the ethanol treatment group. Ethanol caused articular cartilage dysplasia that was programmed in adulthood via a low-functional TGFβ signaling pathway, and the tolerance of this articular cartilage to external stimuli was significantly decreased.