Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.
Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.
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DOI：
10.1371/journal.pone.0092699
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ohno K
中科院分区：
文献类型：
--
作者：
Takamatsu A;Ohkawara B;Ito M;Masuda A;Sakai T;Ishiguro N;Ohno K
在过去的几年中，经典的 Wnt/β-catenin 信号通路已成为软骨发育和体内平衡的关键调节因子。 FRZB 是一种可溶性 Wnt 信号传导拮抗剂，已在骨关节炎 (OA) 动物模型和 OA 患者中作为 Wnt 信号传导调节剂进行了研究。我们筛选了 FDA 批准的诱导 FRZB 表达并抑制 Wnt/β-连环蛋白信号传导的药物。我们发现维拉帕米（一种广泛使用的 L 型钙通道阻滞剂）可升高人 OA 软骨细胞中 FRZB 的表达并抑制 Wnt/β-连环蛋白信号传导。维拉帕米可减弱 OA 软骨细胞中 β-连环蛋白的表达和核转位。在 LiCl 处理和 FRZB 下调的 OA 软骨细胞中缺乏维拉帕米作用也表明维拉帕米通过诱导 FRZB 抑制 Wnt 信号传导。维拉帕米增强了人 OA 软骨细胞中编码聚集蛋白聚糖的 ACAN、编码 II 型胶原 α1 的 COL2A1 和 SOX9 的软骨形成标记物的基因表达，并抑制了 Wnt 反应性 AXIN2 和 MMP3。 Verapamil 可改善软骨分化 ATDC5 细胞中 Wnt3A 诱导的蛋白聚糖损失。维拉帕米抑制小鼠胫骨外植体培养物中软骨细胞的肥大分化。在大鼠 OA 模型中，关节内注射维拉帕米可抑制 OA 进展以及 β-catenin 的核定位。我们认为维拉帕米通过上调 FRZB 并随后下调 Wnt/β-catenin 信号传导而有望成为 OA 的有效治疗剂。
In past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. FRZB, a soluble antagonist of Wnt signaling, has been studied in osteoarthritis (OA) animal models and OA patients as a modulator of Wnt signaling. We screened for FDA-approved drugs that induce FRZB expression and suppress Wnt/β-catenin signaling. We found that verapamil, a widely prescribed L-type calcium channel blocker, elevated FRZB expression and suppressed Wnt/β-catenin signaling in human OA chondrocytes. Expression and nuclear translocation of β-catenin was attenuated by verapamil in OA chondrocytes. Lack of the verapamil effects in LiCl-treated and FRZB-downregulated OA chondrocytes also suggested that verpamil suppressed Wnt signaling by inducing FRZB. Verapamil enhanced gene expressions of chondrogenic markers of ACAN encoding aggrecan, COL2A1 encoding collagen type II α1, and SOX9, and suppressed Wnt-responsive AXIN2 and MMP3 in human OA chondrocytes. Verapamil ameliorated Wnt3A-induced proteoglycan loss in chondrogenically differentiated ATDC5 cells. Verapamil inhibited hypertrophic differentiation of chondrocytes in the explant culture of mouse tibiae. Intraarticular injection of verapamil inhibited OA progression as well as nuclear localizations of β-catenin in a rat OA model. We propose that verapamil holds promise as a potent therapeutic agent for OA by upregulating FRZB and subsequently downregulating Wnt/β-catenin signaling.
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影响因子：
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作者：
Lawrence, Reva C.;Felson, David T.;Wolfe, Frederick
通讯作者：
Wolfe, Frederick
影响因子：
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de Crombrugghe, B
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