Tie Kai, Zhang Xianrong, Tan Yang, Deng Yu, Li Jing, Ni Qubo, Wang Hui, Chen Liaobin
*Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China; Department of Physiology and Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China; and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China.
*Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China; Department of Physiology and Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China; and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China
FASEB J. 2016 Feb;30(2):785-97. doi: 10.1096/fj.15-274399. Epub 2015 Oct 23.
This study aimed to evaluate whether female adult offspring born with intrauterine growth retardation induced by prenatal nicotine exposure (PNE) are susceptible to osteoarthritis (OA) and to explore the underlying programming mechanisms. Pregnant rats were treated with nicotine or saline at 2.0 mg/kg/d from gestational d 11 to 20. The female adult offspring with or without PNE were forced with a strenuous treadmill running for 6 wk to induce OA. Nicotine's effects on fetal articular chondrocytes were studied by exposing chondrocytes to nicotine for 10 d, and dihydro-β-erythroidine, a selective α4β2-nicotinic acetylcholine receptor (nAChR) inhibitor, was used to identify the change of nicotine's effect. For adult offspring, increased cartilage destruction and accelerated OA progression were observed in the PNE group with running; the expression of α1 chain of type II collagen (Col2A1), aggrecan, SRY-type high mobility group box 9 (Sox9), and IGF1 signaling molecules in the cartilage of PNE offspring were decreased. For fetuses, elevated serum corticosteroid and nicotine levels and suppressed IGF1 levels were observed; expression of Col2A1, aggrecan, Sox9, and IGF1 were reduced. The result of chondrocytes revealed that nicotine impeded the expression of Col2A1, aggrecan, and IGF1; blocking α4β2-nAChR rescued nicotine's suppression. In conclusion, PNE increases the susceptibility of adult offspring to OA; the potential mechanism involves IGF1 low-functional programming in articular cartilage caused directly by the action of nicotine on α4β2-nAChR.
本研究旨在评估产前尼古丁暴露（PNE）诱导出生的成年雌性后代是否易患骨关节炎（OA），并探索潜在的编程机制。从妊娠第11天至第20天，对怀孕大鼠以2.0mg/kg/d的剂量给予尼古丁或生理盐水。对有或无PNE的成年雌性后代进行6周的高强度跑步机跑步以诱导OA。通过将软骨细胞暴露于尼古丁10天来研究尼古丁对胎儿关节软骨细胞的影响，并使用选择性α4β2 - 烟碱型乙酰胆碱受体（nAChR）抑制剂二氢-β-刺桐啶来确定尼古丁作用的变化。对于成年后代，在跑步的PNE组中观察到软骨破坏增加和OA进展加速；PNE后代软骨中II型胶原（Col2A1）α1链、聚集蛋白聚糖、SRY型高迁移率族盒9（Sox9）和IGF1信号分子的表达降低。对于胎儿，观察到血清皮质类固醇和尼古丁水平升高以及IGF1水平受到抑制；Col2A1、聚集蛋白聚糖、Sox9和IGF1的表达降低。软骨细胞的结果显示，尼古丁阻碍了Col2A1、聚集蛋白聚糖和IGF1的表达；阻断α4β2 - nAChR可挽救尼古丁的抑制作用。总之，PNE增加了成年后代对OA的易感性；潜在机制涉及尼古丁对α4β2 - nAChR的作用直接导致关节软骨中IGF1功能低下的编程。
