title: Continuous infusion of angiotensin II modulates hypertrophic differentiation and apoptosis of chondrocytes in cartilage formation in a fracture model mouse.
abstract: 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.
authors.affiliation: 1] Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan [2] Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kawahata
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sotobayashi
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Division of Vascular Medicine and Epigenetics, United Graduate School of Child Development, Osaka University, Osaka, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Division of Vascular Medicine and Epigenetics, United Graduate School of Child Development, Osaka University, Osaka, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.affiliation: Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049108:Cell Enlargement / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020219:Chondrogenesis / Q000187:drug effects*; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007262:Infusions, Intravenous; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012253:Rib Fractures / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; D007093:Imidazoles; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D013777:Tetrazoles; D000804:Angiotensin II; C437965:olmesartan; D053509:Matrix Metalloproteinase 13