TGF-β is a potent inducer of Nerve Growth Factor in articular cartilage via the ALK5-Smad2/3 pathway. Potential role in OA related pain?
TGF-β is a potent inducer of Nerve Growth Factor in articular cartilage via the ALK5-Smad2/3 pathway. Potential role in OA related pain?
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DOI：
10.1016/j.joca.2014.12.005
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发表时间：
2015-03-01
影响因子：
7
通讯作者：
van der Kraan, P. M.
中科院分区：
文献类型：
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作者：
Davidson, E. N. Blaney;van Caam, A. P. M.;van der Kraan, P. M.
目的：疼痛是骨性关节炎(OA)患者的主要问题。疼痛与炎症有关，但在骨性关节炎患者中，有一部分患者患有疼痛而没有炎症，这表明疼痛的另一种来源。神经生长因子(NGF)抑制对骨性关节炎疼痛的阻断非常有效，但NGF的来源尚不清楚。我们假设骨关节炎患者受损的软骨释放转化生长因子-β，转化生长因子-β反过来刺激软骨细胞产生神经生长因子。设计：用转化生长因子-β1和/或白介素1(IL-1)刺激小鼠和人软骨细胞系、原代牛和人软骨细胞以及牛掌骨关节和人骨关节炎关节软骨移植。采用定量聚合酶链式反应(QPCR)检测NGF在mRNA水平的表达，免疫组织化学染色检测人骨关节炎软骨中NGF的表达。用TAK1、Smad2/3或Smad1/5/8信号通路阻断剂预先孵育培养细胞，以确定诱导NGF的转化生长因子-β途径。结果：在所有实验中，转化生长因子-β均比IL-1诱导更高水平的NGF表达，无论是小鼠、牛还是人来源，在细胞系、原代软骨细胞和外植体培养中，NGF的表达均高于IL-1。TAK1抑制持续减少转化生长因子-β诱导的神经生长因子，而完全阻断IL-1β诱导的神经生长因子的表达。相反，Alk5-Smad2/3抑制可完全阻断转化生长因子-β诱导的NGF表达。尽管基础NGF在人骨关节炎标本中的表达差异很大(mRNA和组织学)，但转化生长因子-β的暴露导致了持续的高水平的神经生长因子诱导。结论：我们首次发现转化生长因子-β以Alk5-Smad2/3依赖的方式诱导软骨细胞中神经生长因子的表达。这揭示了骨性关节炎疼痛的一个潜在的非炎症性来源。(C)2014国际骨性关节炎研究会。爱思唯尔有限公司出版。保留所有权利。
Objective: Pain is the main problem for patients with osteoarthritis (OA). Pain is linked to inflammation, but in OA a subset of patients suffers from pain without inflammation, indicating an alternative source of pain. Nerve Growth Factor (NGF) inhibition is very efficient in blocking pain during OA, but the source of NGF is unclear. We hypothesize that damaged cartilage in OA releases Transforming Growth Factor-beta (TGF-beta), which in turn stimulates chondrocytes to produce NGF.Design: Murine and human chondrocyte cell lines, primary bovine and human chondrocytes, and cartilage explants from bovine metacarpal joints and human OA joints were stimulated with TGF-beta 1 and/or Interleukin-1 (IL-1)beta. We analyzed NGF expression on mRNA level with QPCR and stained human OA cartilage for NGF immunohistochemically. Cultures were additionally pre-incubated with inhibitors for TAK1, Smad2/3 or Smad1/5/8 signaling to identify the TGF-beta pathway inducing NGF.Results: NGF expression was consistently induced in higher levels by TGF-beta than IL-1 in all of our experiments: murine, bovine and human origin, in cell lines, primary chondrocytes and explants cultures. TAK1 inhibition consistently reduced TGF-beta-induced NGF whereas it fully blocked IL-1 beta-induced NGF expression. In contrast, ALK5-Smad2/3 inhibition fully blocked TGF-beta-induced NGF expression. Despite the large variation in basal NGF in human OA samples (mRNA and histology), TGF-beta exposure led to a consistent high level of NGF induction.Conclusion: We show for the first time that TGF-beta induces NGF expression in chondrocytes, in a ALK5-Smad2/3 dependent manner. This reveals a potential alternative non-inflammatory source of pain in OA. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.