Continuous infusion of angiotensin II modulates hypertrophic differentiation and apoptosis of chondrocytes in cartilage formation in a fracture model mouse
Continuous infusion of angiotensin II modulates hypertrophic differentiation and apoptosis of chondrocytes in cartilage formation in a fracture model mouse
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DOI：
10.1038/hr.2015.18
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发表时间：
2015-06-01
影响因子：
5.4
通讯作者：
Morishita, Ryuichi
中科院分区：
文献类型：
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作者：
Kawahata, Hirohisa;Sotobayashi, Daisuke;Morishita, Ryuichi
尽管肾素-血管紧张素系统(RAS)的组成部分被报道在培养的软骨细胞和软骨中表达，但对血管紧张素II(Ang II)在软骨细胞中的确切功能知之甚少。在本研究中，我们利用小鼠肋骨骨折模型来研究Ang II对软骨细胞的影响。小鼠胫骨生长板软骨细胞表达血管紧张素Ⅱ1型受体(AT1R)。肋骨骨折小鼠持续输注血管紧张素Ⅱ后，软骨体积显著增加，提示血管紧张素Ⅱ诱导软骨细胞肥大分化。与软骨细胞分化相关的Sox9和Runt相关转录因子2(Runx2)以及肥大软骨细胞特异性分子标志物X型胶原、基质金属蛋白酶(MMP13)和印度刺猬(IHH)的mRNA表达显著增加也证实了这一点。通过给予AT1R阻滞剂奥美沙坦，这些基因上调的软骨细胞肥大可以减轻，但不能通过肼来缓解。Ang II可显著抑制软骨细胞的凋亡，并显著诱导bcl2和bclxlmRNA的表达。奥美沙坦可显著减弱血管紧张素转换酶II诱导的凋亡细胞减少和抗凋亡基因表达的增加，但不能显著减轻肼对其的影响。总体而言，本研究表明，Ang II促进了软骨细胞的肥大分化，减少了肥大软骨细胞的凋亡，而不依赖于高血压。提示Ang II在软骨中的作用，可能为软骨疾病的治疗提供新的思路。
Although components of the renin-angiotensin system (RAS) are reported to be expressed in cultured chondrocytes and cartilage, little is known about the precise function of Angiotensin II (Ang II) in chondrocytes. In this study, we employed a rib fracture model mouse to investigate the effect of Ang II on chondrocytes. Ang II type 1 receptor (AT1R) was expressed in chondrocytes in the growth plate of mouse tibia. Continuous infusion of Ang II to rib-fractured mice resulted in a significant increase in the volume of cartilage, suggesting Ang II-induced hypertrophic differentiation of chondrocytes. It was also confirmed by a significant increase in the mRNA expression of Sox9 and runt-related transcription factor 2 (Runx2), which are genes related to chondrocyte differentiation, and type X collagen, matrix metalloproteinase (MMP)-13 and Indian hedgehog (Ihh), which are hypertrophic chondrocyte-specific molecular markers. Chondrocyte hypertrophy with upregulation of these genes was attenuated by administration of olmesartan, an AT1R blocker, but not by hydralazine. Moreover, Ang II infusion significantly suppressed apoptosis of chondrocytes, accompanied by significant induction of mRNA expression of bcl-2 and bcl-xL. Olmesartan, but not hydralazine, significantly attenuated the reduction of apoptotic cells and the increase in anti-apoptotic genes induced by Ang II infusion. Overall, the present study demonstrated that Ang II promoted hypertrophic differentiation of chondrocytes and reduced apoptosis of hypertrophic chondrocytes independently of high blood pressure. The present data indicate the role of Ang II in cartilage, and might provide a new concept for treatment of cartilage diseases.