Sympathetic denervation-induced MSC mobilization in distraction osteogenesis associates with inhibition of MSC migration and osteogenesis by norepinephrine/adrb3.
Sympathetic denervation-induced MSC mobilization in distraction osteogenesis associates with inhibition of MSC migration and osteogenesis by norepinephrine/adrb3.
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牵张成骨过程中交感神经去神经诱导的 MSC 动员与去甲肾上腺素/adrb3 抑制 MSC 迁移和成骨有关
DOI：
10.1371/journal.pone.0105976
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Lei D
中科院分区：
文献类型：
--
作者：
Du Z;Wang L;Zhao Y;Cao J;Wang T;Liu P;Zhang Y;Yang X;Cheng X;Liu B;Lei D
交感神经系统在生理条件下调节骨的形成和吸收。然而，交感神经如何影响骨再生中干细胞的迁移和分化仍不清楚。牵张成骨是一种理想的骨再生模型。本研究采用大鼠下颌骨牵张成骨颈交感神经干切断模型，观察去交感神经可减少牵张骨痂中去甲肾上腺素（NE），下调骨髓间充质干细胞（MSCs）中β3肾上腺素能受体（adrb 3），促进MSCs从血管周围向成骨单位迁移。体外Transwell实验证实NE可抑制基质衍生因子-1（SDF-1）诱导的MSC迁移和迁移相关基因基质金属蛋白酶-2（MMP-2）的表达，下调抗迁移基因组织金属蛋白酶抑制剂-3（TIMP-3）的表达。使用siRNA敲低adrb 3消除了对MSC迁移的抑制。体外成骨实验表明NE可抑制MSC骨结节的形成以及成骨标志基因碱性磷酸酶（ALP）、骨钙素（OCN）和runt-related transcription factor-2（RUNX 2）的表达，但通过siRNA敲低adrb 3可消除这种对MSC成骨分化的抑制。因此，去交感神经诱导的MSC在大鼠下颌骨牵张成骨中的动员与NE/adrb 3抑制MSC迁移和成骨分化有关。这些发现可能有助于理解MSC动员和交感神经系统在广泛的组织再生过程中的关系。
The sympathetic nervous system regulates bone formation and resorption under physiological conditions. However, it is still unclear how the sympathetic nerves affect stem cell migration and differentiation in bone regeneration. Distraction osteogenesis is an ideal model of bone regeneration due to its special nature as a self-engineering tissue. In this study, a rat model of mandibular distraction osteogenesis with transection of cervical sympathetic trunk was used to demonstrate that sympathetic denervation can deplete norepinephrine (NE) in distraction-induced bone callus, down-regulate β3-adrenergic receptor (adrb3) in bone marrow mesenchymal stem cells (MSCs), and promote MSC migration from perivascular regions to bone-forming units. An in vitro Transwell assay was here used to demonstrate that NE can inhibit stroma-derived factor-1 (SDF-1)-induced MSC migration and expression of the migration-related gene matrix metalloproteinase-2 (MMP-2) and downregulate that of the anti-migration gene tissue inhibitor of metalloproteinase-3 (TIMP-3). Knockdown of adrb3 using siRNA abolishes inhibition of MSC migration. An in vitro osteogenic assay was used to show that NE can inhibit the formation of MSC bone nodules and expression of the osteogenic marker genes alkaline phosphatase (ALP), osteocalcin (OCN), and runt-related transcription factor-2 (RUNX2), but knockdown of adrb3 by siRNA can abolish such inhibition of the osteogenic differentiation of MSCs. It is here concluded that sympathetic denervation-induced MSC mobilization in rat mandibular distraction osteogenesis is associated with inhibition of MSC migration and osteogenic differentiation by NE/adrb3 in vitro. These findings may facilitate understanding of the relationship of MSC mobilization and sympathetic nervous system across a wide spectrum of tissue regeneration processes.
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DOI：
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