Norepinephrine Inhibits Synovial Adipose Stem Cell Chondrogenesis via α2a-Adrenoceptor-Mediated ERK1/2 Activation
Norepinephrine Inhibits Synovial Adipose Stem Cell Chondrogenesis via α2a-Adrenoceptor-Mediated ERK1/2 Activation
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DOI：
10.3390/ijms20133127
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Jenei-Lanzl, Zsuzsa
中科院分区：
文献类型：
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作者：
El Bagdadi, Karima;Zaucke, Frank;Jenei-Lanzl, Zsuzsa
近年来，首次有证据表明交感神经递质影响骨关节炎的临床表现。关节内干细胞可能有助于软骨修复，但其软骨形成功能降低。对创伤和骨性关节炎患者滑液中神经递质去甲肾上腺素(NE)进行了检测。因此，本研究的目的是分析去甲肾上腺素如何影响滑膜脂肪组织来源干细胞(SASCs)的软骨形成。从膝关节骨性关节炎患者的滑膜中分离出sASCs。在肾上腺素受体(AR)表达分析后，观察去甲肾上腺素(NE)和/或α-和β-AR拮抗剂对软骨细胞增殖和向软骨细胞分化的影响。检测细胞计数、细胞存活率、软骨形成和细胞增殖基因表达、硫酸糖胺多聚糖(SGAG)和II型胶原含量。免疫印迹分析关键的AR依赖信号(ERK1/2，PKA)。SASC在单层和颗粒培养中表达α1a、α1B、α2a、α2b、α2c和β2-AR。10(-7)和10(-6)的去甲肾上腺素可显著降低SGAG和II型胶原的含量以及ERK1/2的磷酸化。这些作用可被α2-AR拮抗剂育亨宾完全逆转。我们的研究证实了去甲肾上腺素在SASC软骨形成功能中的重要作用，并为骨性关节炎的病理生理学提供了新的见解。未来的研究可能有助于开发针对OA治疗的神经内分泌通路的新的治疗方案。
In recent years, first evidences emerged that sympathetic neurotransmitters influence osteoarthritis (OA) manifestation. Joint-resident stem cells might contribute to cartilage repair, however, their chondrogenic function is reduced. The neurotransmitter norepinephrine (NE) was detected in the synovial fluid of trauma and OA patients. Therefore, the aim of this study was to analyse how NE influences the chondrogenesis of synovial adipose tissue-derived stem cells (sASCs). sASCs were isolated from knee-OA patients synovia. After adrenoceptor (AR) expression analysis, proliferation and chondrogenic differentiation in presence of NE and/or alpha- and beta-AR antagonist were investigated. Cell count, viability, chondrogenic and hypertophic gene expression, sulfated glycosaminoglycan (sGAG) and type II collagen content were determined. Key AR-dependent signaling (ERK1/2, PKA) was analyzed via western blot. sASC expressed alpha 1A-, alpha 1B-, alpha 2A-, alpha 2B-, alpha 2C-, and beta 2-AR in monolayer and pellet culture. NE did not affect proliferation and viability, but 10(-7) and 10(-6) M NE significantly reduced sGAG and type II collagen content as well as ERK1/2 phosphorylation. These effects were fully reversed by yohimbine (alpha 2-AR antagonist). Our study confirms the important role of NE in sASC chondrogenic function and provides new insights in OA pathophysiology. Future studies might help to develop novel therapeutic options targeting neuroendocrine pathways for OA treatment.