PNAS：研究显示吸烟如何导致骨质疏松

正常情况下，人类的骨骼一直在进行着降解和再生，两者完美的平衡使得骨骼肌强度保持稳定。

随着年龄的增长，骨骼降解过程变快，导致骨质疏松和其他类型疾病。而吸烟会加快骨骼退化过程。

宾夕法尼亚大学科学家和西奈山医学中心科学家首次揭示了香烟中的哪些物质导致了骨骼退化。相关报道发表在近期PNAS上。
Narayan Avadhani博士表示，很多流行病学研究都表明吸烟者骨密度比不吸烟者的骨密度要低，我们揭示了香烟哪些成分引起骨质疏松。

在正常情况下，一种称之为成骨细胞的细胞建立新的骨骼，而另一类破骨细胞则降解骨基质，该过程称之为骨重塑。RANK配体是一种调节性分子，该分子就决定了成骨细胞和破骨细胞的活性。

科学家已知吸烟者的骨骼退化速率比不吸烟者要快，长此以往就导致了骨质疏松，但是其背后的机制仍然不知道。

研究发现当香烟中的特殊分子结合机体内的芳香烃受体（AH-receptors）后，会产生过多的破骨细胞，而过多的破骨细胞导致吸烟者骨质疏松。

科学家用小鼠模型检测了香烟中的毒性成分苯并芘和TCDD骨骼的影响。他们发现AH受体能够激活一类称之为Cyp1的细胞色素P450酶。当下调编码Cyp1的基因时，AH受体不能引起破骨细胞形成，从而有效的避免了骨质疏松。因此Cyp1基因在吸烟引起骨质疏松过程中扮演了重要的角色。

研究人员也惊异的发现RANK配体也是诱导破骨细胞形成的关键分子，而且该配体是通过AH受体介导的。

研究表明针对AH受体设计分子有望治疗吸烟者和非吸烟者的骨质疏松疾病。研究人员也表示由于激活AH受体也影响了机体其它组织，所以靶向针对骨骼是该分子药物成功的关键。

原文链接：

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Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes

Smoking is a major risk factor for osteoporosis and fracture, but the mechanism through which smoke causes bone loss remains unclear. Here, we show that the smoke toxins benzo(a)pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interact with the aryl hydrocarbon receptor (Ahr) to induce osteoclastic bone resorption through the activation of cytochrome P450 1a/1b (Cyp1) enzymes. BaP and TCDD enhanced osteoclast formation in bone marrow cell cultures and gavage with BaP stimulated bone resorption and osteoclastogenesis in vivo. The osteoclastogenesis triggered by BaP or RANK-L was reduced in Ahr?/? cells, consistent with the high bone mass noted in Ahr?/? male mice. The receptor activator of NF-κB ligand (RANK-L) also failed to induce the expression of Cyp1 enzymes in Ahr?/? cells. Furthermore, the osteoclastogenesis induced by TCDD was lower in Cyp1a1/1a2?/? and Cyp1a1/1a2/1b1?/? cultures, indicating that Ahr was upstream of the Cyp enzymes. Likewise, the pharmacological inhibition of the Cyp1 enzymes with tetramethylsilane or proadifen reduced osteoclastogenesis. Finally, deletion of the Cyp1a1, Cyp1a2, and Cyp1b1 in triple knockout mice resulted in reduced bone resorption and recapitulated the high bone mass phenotype of Ahr?/? mice. Overall, the data identify the Ahr and Cyp1 enzymes not only in the pathophysiology of smoke-induced osteoporosis, but also as potential targets for selective modulation by new therapeutics.





来源：生物谷