Cyclic compressive loading activates angiotensin II type 1 receptor in articular chondrocytes and stimulates hypertrophic differentiation through a G-protein-dependent pathway.
Cyclic compressive loading activates angiotensin II type 1 receptor in articular chondrocytes and stimulates hypertrophic differentiation through a G-protein-dependent pathway.
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DOI：
10.1002/2211-5463.12438
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发表时间：
2018-06
期刊：
影响因子：
2.6
通讯作者：
Akagi M
中科院分区：
文献类型：
--
作者：
Nakamura F;Tsukamoto I;Inoue S;Hashimoto K;Akagi M
血管紧张素II 1型受体（AT 1 R）似乎在许多细胞类型中具有机械感受功能。本研究的目的是检查是否AT 1 R在关节软骨细胞中表达参与骨关节炎（OA）的进展，在体内和是否周期性压缩负荷激活AT 1 R，刺激肥大分化的软骨细胞在体外。在使用内侧半月板不稳定模型诱导的OA小鼠膝关节中研究了软骨退变的改良Mankin评分与AT 1 R和X型胶原（Col X）表达之间的关系。对三维琼脂糖支架中培养的牛关节软骨细胞施加循环压缩载荷。使用RT-PCR和蛋白质印迹分析Col X和runt相关转录因子2（Runx 2）的表达。我们剖析了AT 1 R细胞内信号转导的下游途径，包括G蛋白依赖性和G蛋白非依赖性途径。Mankin评分与AT 1 R免疫阳性细胞率之间以及AT 1 R与Col X表达率之间存在显著正相关。Col X和Runx 2的表达增加压缩负荷，但抑制奥美沙坦，血管紧张素II受体阻断剂，琼脂糖支架。压缩负荷上调c-Jun N-末端激酶（JNK）、Src和STAT 1的磷酸化，但奥美沙坦仅显著抑制JNK磷酸化。我们的结论是，关节软骨细胞表达的AT 1 R可能参与了体内OA的进展。机械应力可以激活AT 1 R并通过G蛋白依赖性途径刺激软骨细胞的肥大分化。AT 1 R在软骨细胞中具有机械敏感功能，可能成为OA治疗的新靶点。
Angiotensin II type 1 receptor (AT1R) appears to have a mechanosensing function in a number of cell types. The purpose of this study was to examine whether AT1R expressed in articular chondrocytes is involved in osteoarthritis (OA) progression in vivo and whether cyclic compressive loading activates the AT1R and stimulates hypertrophic differentiation of chondrocytes in vitro. The relationships between the modified Mankin score for cartilage degeneration and the expression of AT1R and type X collagen (Col X) were studied in mouse knees with OA induced using the destabilization‐of‐medial‐meniscus model. Cyclic compressive loads were applied to cultured bovine articular chondrocytes in three‐dimensional agarose scaffolds. Expression of Col X and runt‐related transcription factor 2 (Runx2) was analyzed using RT‐PCR and western blotting. We dissected the downstream pathway for intracellular signal transductions of AT1R including G‐protein‐dependent and G‐protein‐independent pathways. Positive significant correlations between the Mankin score and the rate of AT1R‐immunopositive cells and between the rates of AT1R and Col X expression were noted. The expression of Col X and Runx2 was increased by compressive loading but suppressed by addition of olmesartan, an Ang II receptor blocker, to the agarose scaffolds. Compressive loading upregulated the phosphorylation of c‐Jun N‐terminal kinase (JNK), Src, and STAT1, but olmesartan significantly suppressed only JNK phosphorylation. We conclude that AT1R expressed by articular chondrocytes may be involved in OA progression in vivo. Mechanical stress can activate AT1R and stimulate hypertrophic differentiation of chondrocytes through the G‐protein‐dependent pathway. AT1R has a mechanosensing function in chondrocytes and may be a new therapeutic target in OA.
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影响因子：
4.9
作者：
Kuroki, Hiroshi;Nakagawa, Yasuaki;Mori, Koji;Ohba, Mao;Suzuki, Takashi;Mizuno, Yasuyuki;Ando, Keiji;Takenaka, Makoto;Ikeuchi, Ken;Nakamura, Takashi
通讯作者：
Nakamura, Takashi
影响因子：
2.4
作者：
Knight, MM;Toyoda, T;Bader, DL
通讯作者：
Bader, DL
影响因子：
7.3
作者：
Garcia, P.;Schwenzer, S.;Menger, M. D.
通讯作者：
Menger, M. D.
影响因子：
7
作者：
Im, GI;Shin, YW;Lee, KB
通讯作者：
Lee, KB
影响因子：
7
作者：
Glasson, S. S.;Blanchet, T. J.;Morris, E. A.
通讯作者：
Morris, E. A.