RESUMEN
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.
Asunto(s)
Diferenciación Celular , Condrocitos/citología , Condrocitos/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Huesos/efectos de los fármacos , Huesos/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Condrocitos/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Embrión de Mamíferos/citología , Embrión de Mamíferos/efectos de los fármacos , Embrión de Mamíferos/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas de Homeodominio/metabolismo , Ratones , FN-kappa B/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tretinoina/farmacología , Proteínas de Unión al GTP rho/metabolismoRESUMEN
Since the fee for orthodontic treatment of malocclusion caused by cleft lip and palate (CLP) became covered by national health insurance in 1982, orthodontic treatment from school age has become the norm. However, in some CLP patients, orthodontic treatment is commenced in adulthood. A number of studies have reported on orthodontic treatment in adult CLP patients. The purpose of this study was to clarify the number and age of new patients, chief complaint, referral status, cleft type, malocclusion, history of orthodontic treatment, and acceptance and planning of orthodontic treatment. The study investigated new CLP patients aged over 18 years who visited the Department of Orthodontics, Suidobashi Hospital of Tokyo Dental College, between April 1, 2001 and March 31, 2006. During the investigation period mentioned above, 235 new CLP patients visited our department. Among them, 23 were aged over 18 years, accounting for 9.8% of the 235 CLP patients. In terms of chief complaint, occlusion-related complaints and occlusal dysfunction accompanying malocclusion were noted in 14 cases (61%). Eighteen patients were referrals. Unilateral CLP was the most prevalent cleft type. In terms of malocclusion type, reversed occlusion was noted in 13 cases (57%), accounting for over half of all cases. Patients with a previous history of orthodontic treatment accounted for half of all cases. Ten patients accepted orthodontic treatment. In terms of treatment plan, surgical orthodontic treatment was planned in 10 cases.
