Activating types 1 and 2 angiotensin II receptors modulate the hypertrophic differentiation of chondrocytes

Tsukamoto, Ichiro; Inoue, Shuhei; Teramura, Takeshi; Takehara, Toshiyuki; Ohtani, Kazuhiro; Akagi, Masao

doi:10.1016/j.fob.2013.07.001

Cited by 16 publications

(19 citation statements)

References 24 publications

(30 reference statements)

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“…ACE expression is induced in the chondrocytes of bone callus during fracture healing, which suggests AngII signaling is involved in endochondral bone formation. Recently, Tsukamoto group showed that Atgr1 suppressed the hypertrophic differentiation of chondrocytes in vitro [35], which is consistent with our observation that blockage of Agtr1 accelerated hypertrophic differentiation during endochondral bone formation. The accelerated hypertrophy in Losartan treated growth plates may be attributed to alteration in the expression of matrix protein like Col10a1, or may be due to changes in matrix protein metabolism, which was suggested by AngII regulation on matrix metalloproteinase during cardiac remodeling or hypertension [36–38].…”

Section: Discussionsupporting

confidence: 91%

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Chen

Grover

Sibai

et al. 2015

Molecular Genetics and Metabolism

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Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development.

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Section: Discussionsupporting

confidence: 91%

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Chen

Grover

Sibai

et al. 2015

Molecular Genetics and Metabolism

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“…However, in contrast to bone, little is known about the effects of Ang II on chondrocytes and cartilage despite the existence of Ang II receptors in chondrocytes. 12,13 Various reports suggest the importance of RAS in chondrocytes. An anti-arthritic effect of blockade of RAS by ARBs has been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Although there is no report indicating the role of AT2R in vivo, previous in vitro experiments using ATDC5 demonstrated that activation of AT2R enhanced hypertrophic differentiation. 13 It was demonstrated that stimulation by Ang II and activation of AT1R suppressed hypertrophic differentiation of chondrocytes. This is the opposite result to our present data.…”

Section: Discussionmentioning

confidence: 99%

“…11 However, the effects of Ang II on chondrocytes and cartilage metabolism are still unclear, although Ang II receptors were shown to be expressed in cultured chondrocytes 12,13 and chondrocytes in vivo. 14 Some papers reported a beneficial effect of an angiotensin converting enzyme inhibitor (ACEI) or an Ang II receptor blocker (ARB) on fracture healing 15,16 in basic experiments, suggesting involvement of RAS in chondral metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Continuous infusion of angiotensin II modulates hypertrophic differentiation and apoptosis of chondrocytes in cartilage formation in a fracture model mouse

et al. 2015

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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.

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“…Angiotensin converting enzyme 2 (ACE2) converts angiotensin Ⅱ (AngⅡ) into peptides including angiotensin-1-7 (Ang1-7) and angiotensin-1-9 that counteract the effects of Ang Ⅱ through Mas receptor (MasR) and angiotensin type II receptor (AT2R) respectively [8, 9]. ACE2 activity and expression level were reported to be severely down regulated or absent in proliferating alveolar epithelial cell lines A549 and MLE-12, while its activity and expression level went much higher in quiescent A549 and MLE-12 cells [10].…”

Section: Introductionmentioning

confidence: 99%

A Human Long Non-Coding RNA ALT1 Controls the Cell Cycle of Vascular Endothelial Cells Via ACE2 and Cyclin D1 Pathway

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: ALT1 is a novel long non-coding RNA derived from the alternatively spliced transcript of the deleted in lymphocytic leukemia 2 (DLEU2). To date, ALT1 biological roles in human vascular endothelial cells have not been reported. Methods: ALT1 was knocked down by siRNAs. Cell proliferation was analyzed by cck-8. The existence and sequence of human ALT1 were identified by 3’ rapid amplification of cDNA ends. The interaction between lncRNA and proteins was analyzed by RNA-Protein pull down assay, RNA immunoprecipitation, and mass spectrometry analysis. Results: ALT1 was expressed in human umbilical vein endothelial cells (HUVECs). The expression of ALT1 was significantly downregulated in contact-inhibited HUVECs and in hypoxia-induced, growth-arrested HUVECs. Knocking down of ALT1 inhibited the proliferation of HUVECs by G0/G1 cell cycle arrest. We observed that angiotensin converting enzyme Ⅱ(ACE2) was a direct target gene of ALT1. Knocking-down of ALT1 or its target gene ACE2 could efficiently decrease the expression of cyclin D1 via the enhanced ubiquitination and degradation, in which HIF-1α and protein von Hippel-Lindau (pVHL) might be involved. Conclusion: The results suggested the human long non-coding RNA ALT1 is a novel regulator for cell cycle of HUVECs via ACE2 and cyclin D1 pathway.

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Activating types 1 and 2 angiotensin II receptors modulate the hypertrophic differentiation of chondrocytes

Cited by 16 publications

References 24 publications

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Continuous infusion of angiotensin II modulates hypertrophic differentiation and apoptosis of chondrocytes in cartilage formation in a fracture model mouse

A Human Long Non-Coding RNA ALT1 Controls the Cell Cycle of Vascular Endothelial Cells Via ACE2 and Cyclin D1 Pathway

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