title: RAGE, receptor of advanced glycation endoproducts, negatively regulates chondrocytes differentiation.
abstract: RAGE, receptor for advanced glycation endoproducts (AGE), has been characterized as an activator of osteoclastgenesis. However, whether RAGE directly regulates chondrocyte proliferation and differentiation is unclear. Here, we show that RAGE has an inhibitory role in chondrocyte differentiation. RAGE expression was observed in chondrocytes from the prehypertrophic to hypertrophic regions. In cultured cells, overexpression of RAGE or dominant-negative-RAGE (DN-RAGE) demonstrated that RAGE inhibited cartilaginous matrix production, while DN-RAGE promoted production. Additionally, RAGE regulated Ihh and Col10a1 negatively but upregulated PTHrP receptor. Ihh promoter analysis and real-time PCR analysis suggested that downregulation of Cdxs was the key for RAGE-induced inhibition of chondrocyte differentiation. Overexpression of the NF-κB inhibitor I-κB-SR inhibited RAGE-induced NF-κB activation, but did not influence inhibition of cartilaginous matrix production by RAGE. The inhibitory action of RAGE was restored by the Rho family GTPases inhibitor Toxin B. Furthermore, inhibitory action on Ihh, Col10a1 and Cdxs was reproduced by constitutively active forms, L63RhoA, L61Rac, and L61Cdc42, but not by I-κB-SR. Cdx1 induced Ihh and Col10a1 expressions and directly interacted with Ihh promoter. Retinoic acid (RA) partially rescued the inhibitory action of RAGE. These data combined suggests that RAGE negatively regulates chondrocyte differentiation at the prehypertrophic stage by modulating NF-κB-independent and Rho family GTPases-dependent mechanisms.
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Rino
authors.initials: R
authors.lastname: Fukui
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kurosaka
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Tanabe
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Takakura
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Waki
authors.affiliation: Molecular Toxicology lab, Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C491272:Cdx1 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C514061:ihh protein, mouse; D014212:Tretinoin; D020741:rho GTP-Binding Proteins