Aryl hydrocarbon receptor-mediated impairment of chondrogenesis and fracture healing by cigarette smoke and benzo(a)pyrene.
Aryl hydrocarbon receptor-mediated impairment of chondrogenesis and fracture healing by cigarette smoke and benzo(a)pyrene.
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DOI：
10.1002/jcp.22819
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发表时间：
2012-03
影响因子：
5.6
通讯作者：
Zuscik, Michael J.
中科院分区：
文献类型：
--
作者：
Kung, Ming H.;Yukata, Kiminori;O'Keefe, Regis J.;Zuscik, Michael J.
临床文献强烈表明，吸烟者的骨骼愈合受到损害。由于香烟烟雾(CS)中含有大量的多环芳烃(PAHs)，以及二恶英通过芳香烃受体(AHR)抑制体内的骨形成，我们研究了PAH/AHR信号在小鼠胫骨骨折模型中对软骨形成和愈合的影响。我们证实，CS通过上调AHR靶基因细胞色素p4501A1(Cyp1A1)来激活骨折中的AHR信号。在体外研究中，我们采用了小鼠肢芽微团软骨形成模型。在确认软骨细胞在分化过程中表达促肾上腺皮质激素受体后，我们用在CS、苯并(α)芘(BaP)或香烟烟雾提取物(CSE)中发现的典型多环芳烃处理细胞。BaP和CSE均强烈抑制E11肢芽培养的间充质细胞的软骨形成，BaP也促进E12肢芽培养的软骨细胞肥大。对BaP处理的培养物中DNA加合物的检测表明，BaP的不同表型效应可能是由于形成了反应性代谢物。用AHR拮抗剂MNF阻断AHR信号可逆转BaP的作用，但不能逆转CSE的作用，提示CSE对软骨形成的抑制不依赖于AHR。与这些结果相关的是，与赋形剂对照组相比，BaP处理的小鼠的胫骨骨折骨痂更小，矿化组织也更少。总体而言，BaP被认为是一种有效的体外软骨形成抑制剂，其对骨折愈合的相关作用与CS本身相似，提示多环芳烃是CS影响骨折修复的关键化合物的基础。
The clinical literature strongly suggests that bone healing in cigarette smokers is impaired. Since cigarette smoke (CS) contains numerous polycyclic aromatic hydrocarbons (PAHs), and since dioxins impair bone formation in vivo via the Aryl Hydrocarbon Receptor (AHR), we investigated the impact of PAH/AHR signaling on chondrogenesis and on healing in a mouse tibial fracture model. We established that CS activates AHR signaling in fractures by up-regulating the AHR target gene cytochrome p4501A1 (Cyp1A1). For in vitro studies, we employed the mouse limb bud micromass chondrogenesis model. After confirming that chondrocytes express AHR during differentiation, we treated cells with a prototypical PAH found in CS, benzo(α)pyrene (BaP), or cigarette smoke extract (CSE). Both BaP and CSE both strongly inhibited chondrogenesis in mesenchymal cells generated from E11 limb buds, with BaP also accelerating chondrocyte hypertrophy in cultures generated from E12 limb buds. Detection of DNA adducts in the BaP-treated cultures suggests that the distinct phenotypic effects of BaP may be due to the formation of reactive metabolites. Blockade of AHR signaling with the AHR antagonist MNF reverses the effects of BaP, but not CSE, suggesting that CSE inhibition of chondrogenesis is AHR-independent. Correlating with these results, tibial fracture calluses from BaP-treated mice were smaller and contained less mineralized tissue than vehicle controls. Overall, BaP is identified as a potent inhibitor of chondrogenesis in vitro with correlated effects on fracture healing similar to those of CS itself, suggesting a basis for PAHs as key compounds in the influence of CS on fracture repair.
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通讯作者：
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