Role of 11beta-hydroxysteroid dehydrogenase in bone metabolism

doi:10.3969/j.issn.2095-4344.2017.32.020

Abstract

Abstract:

BACKGROUND: Glucocorticoids play an essential role in osteoblast differentiation, but excessive glucocorticoids will inhibit the osteoblastic phenotype. Regulation of 11β-hydroxysteroid dehydrogenase (11β-HSD) contributes to optimizing the effect of glucocorticoids.
OBJECTIVE: To summarize the effect of 11β-HSD in bone metabolism.
METHODS: The corresponding author retrieved PubMed and CJFD databases for the articles published before 2016 using the keywords “11β-HSD, bone” in English and Chinese, respectively. Totally 115 articles were retrieved, including 98 English and 17 Chinese articles, and finally 45 eligible articles were included in accordance with the inclusion criteria.
RESULTS AND CONCLUSION: Glucocorticoid action can be regulated at prereceptor level by 11β-HSD. 11β-HSD1 activity may predict individual susceptibility to glucocorticoids, which instructs the individualized application of glucocorticoids precisely. 11β-HSD1 activity is closely related to osteoblast differentiation and the presence of an intrinsic differentiation-driven molecular switch inhibits the activity of 11β-HSD1. Instead of regulating the mesenchymal progenitors directly, gucocorticoids regulate the mesenchymal progenitors to differentiate into cranial skeleton mainly through mature osteoblasts. Short-term glucocorticoid exposure directly increases 11β-HSD1 activity and continuous exposure to glucocorticiod indirectly inhibits 11β-HSD1 activity.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Metabolism, Glucocorticiods, Bone and Bones, Tissue Engineering

CLC Number:

R318

Han Jun1, Sun Wei2, Gao Fu-qiang2. Role of 11beta-hydroxysteroid dehydrogenase in bone metabolism[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(32): 5203-5206.

Figures/Tables 1

2 结果 Results 2.1 11β-HSD的基本结构及对糖皮质激素的调节 11β-HSD属于短肽链乙醇氧化还原酶家族，以N-末端结合于特定细胞的内质网上，另外接触反应区还存在一个佪文结构，类似于于糖皮质激素的反应位点。该酶分为两型，即11β-HSD1和11β-HSD2。11β-HSD1有292个氨基酸，相对分子质量为34×103。11β-HSD1在多肽链上有两个糖基化位点，糖基化抑制剂可削弱11β-HSD1的脱氢酶功能，但不影响还原酶功能[7]。人类11β-HSD2有405个氨基酸，相对分子质量约为40×103。11β-HSD2在人体中发挥脱氢酶的作用，目前未发现具有还原酶作用的11β-HSD2。11β-HSD2结构中也有一两个潜在的糖基化位点，由于其周围存在脯氨酸，因此被糖基化的可能性很小[8]。由于11β-HSD 1和11β-HSD 2的催化功能不同,两者在体内的分布具有鲜明的特点。11β-HSD 1主要分布于成骨细胞和破骨细胞中[9]，11β-HSD 2则主要分布于正常胎儿骨骼和骨肉瘤细胞中[9-10]。11β-HSD 1具有氧化和还原的双重催化作用, 在骨细胞完整情况下主要发挥还原酶作用，可以将细胞内的无活性的皮质酮还原成有活性的皮质醇，所以11β-HSD 1又被称为“糖皮质激素效应的扩大器”。11β-HSD 2为专一的氧化酶，它通过氧化作用使糖皮质激素失活，从而降低细胞局部的糖皮质激素浓度。11β-HSD 1和11β-HSD 2两者共同作用，使细胞局部的糖皮质激素浓度达到生理平衡状态，从而维持糖皮质激素对正常骨代谢的生理作用。 2.2 11β-HSD 调控骨代谢的生理机制因为11β-HSD在成骨细胞和破骨细胞中都有分布，通过对糖皮质激素活性的调节，可以对骨代谢的整个过程进行调节，影响骨骼的生长发育，因而11β-HSD对于维持骨代谢的正常运转非常的重要[11]。11β-HSD 1的活性和11β-HSD 1 mRNA表达量与成骨标志物的水平有密切关系[12]。以往的研究发现，个体对糖皮质激素敏感度(即：成骨标志物水平的下降程度)的差异化，与循环血液的糖皮质激素浓度及骨细胞表面糖皮质激素受体的分布密度都无明显关联[13-15]。Cooper等[12]研究发现，11β-HSD 1的活性与个体对糖皮质激素的敏感度呈正比例关系，Cooper等[12]对20名健康的志愿者首先进行基础11β-HSD 1活性的测定，然后每人每次口服5 mg泼尼松龙，2次/d，持续 7 d。发现志愿者血清中的成骨标志物水平明显下降，而破骨标志物水平变化不大，成骨标志物的下降趋势与服用激素前11β-HSD 1的活性趋势呈正比例关系，但与11β-HSD 2的活性趋势没有比例关系。11β-HSD1在破骨细胞中亦有分布，Kaji等[16]认为，糖皮质激素对破骨细胞的分化有重要的促进作用，根据Cooper等[17]的研究发现，志愿者服用11β-HSD非特异性抑制剂甘珀酸后，骨吸收标志物下降明显，而骨形成标志物无明显改变。Park等[18]应用特异性11β-HSD1抑制剂KR-67500之后，实验小鼠体内也出现了与上述实验结果一样的变化。11β-HSD1作为一种还原酶，对于提高破骨细胞内的糖皮质激素水平有重要作用，而甘珀酸抑制了11β-HSD1的活动后，将会减弱对糖皮质激素的活化作用，从而导致骨吸收标志下降。成骨细胞的11β-HSD 1活性与其分化活跃度密切相关。Eijken等[19]研究发现其两者呈反比例关系，他们应用人前成骨细胞株(SV-HFO)进行体外实验，实验分为加有1 μmol地塞米松培养基的实验组(分化组)和不含地塞米松培养基的对照组(非分化组)，培养23 d后测定每组碱性磷酸酶(成骨细胞的分化活跃度)的含量，发现实验组的碱性磷酸酶含量更高，所以地塞米松对前成骨细胞具有促分化作用(见图2)。此后，分别测定2组的11β-HSD 1分化程度(在培养7，12，14，19 d时，各添加1 μmol/L的可的松，以测定每组的11β-HSD 1的活性)，发现不含地塞米松组的11β-HSD 1的活性更高，所以前成骨细胞的分化活跃度与11β-HSD 1的活性成反比例关系(见图3)，11β-HSD 1可以反馈调节前成骨细胞局部的糖皮质激素的浓度，以此达到糖皮质激素的浓度平衡，从而维持正常的骨代谢[19]。为了进一步验证这一结论，Eijken等[19]又将SV-HFO分别在不同浓度梯度的地塞米松条件下培养19 d，发现碱性磷酸酶水平呈激素浓度依赖性升高，同时，11β-HSD 1的活性呈激素浓度依赖性降低。然而，有些研究发现，11β-HSD 1的活性与糖皮质激素的浓度呈正比[20-21]，但Eijken等[19]学者认为，11β-HSD 1的活性与糖皮质激素的浓度之间的关系分两种情况，第1种情况是SV-HFO短期暴露于地塞米松的条件下，地塞米松可以直接促进11β-HSD 1 mRNA的表达。第2种情况则是SV-HFO长期暴露于地塞米松的条件下，地塞米松通过促进SV-HFO的分化，从而间接抑制了11β-HSD 1 mRNA的表达。Eijken等用无地塞米松培养基培养的SV-HFO做了两组短期暴露对照实验，第1组对照试验是测定11β-HSD 1 mRNA的相对表达量组(见图4A)，第2组对照试验是测定11β-HSD 1 的活性组(见图4B)，见表1。结果显示，培养12 d之后的SV-HFO，短期的地塞米松暴露可以促进11β-HSD 1的表达。而对于培养第7天时，短期暴露于地塞米松的SV-HFO，其11β-HSD 1 mRNA表达量下降是因为SV-HFO在7d内对于糖皮质激素诱导分化的敏感性很高，从而高分化活跃度抑制了11β-HSD 1 mRNA表达量，12 d之后的11β-HSD 1 mRNA表达量升高则是糖皮质激素的直接刺激导致。 11β-HSD 2的活性影响成骨细胞的发育及成熟。研究表明组织局部活性糖皮质激素浓度在间叶细胞分化为成熟的成骨细胞中起到了关键作用[22-23]。但是，从Col2.3-11β-HSD2转基因小鼠实验(阻断糖皮质激素信号通路)得到的证据显示，糖皮质激素不是直接作用于间叶细胞，而是以成熟成骨细胞作为中间媒介[24]，间接作用于间叶细胞。比如，对取自Col2.3-11β-HSD2转基因小鼠的颅骨组织进行培养，与具有完好糖皮质激素通路的野生型小鼠相比较，表现为间叶细胞倾向于向脂肪细胞分化，而分化为成骨细胞的数量减少。在异常表型的 "

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