RESUMEN
Bone formation is controlled by a network of transcription factors and signaling molecules. In this issue, , studying the role of the transcription factor ATF4 in a new mouse model of neurofibromatosis type I skeletal defects, demonstrate striking effects of changing dietary protein on bone formation abnormalities.
Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Enfermedades del Desarrollo Óseo/dietoterapia , Enfermedades del Desarrollo Óseo/metabolismo , Proteínas en la Dieta/uso terapéutico , Neurofibromina 1/metabolismo , Osteoblastos/metabolismo , Aminoácidos/metabolismo , Animales , Transporte Biológico Activo/efectos de los fármacos , Transporte Biológico Activo/genética , Enfermedades del Desarrollo Óseo/congénito , Enfermedades del Desarrollo Óseo/patología , Resorción Ósea/dietoterapia , Resorción Ósea/genética , Resorción Ósea/metabolismo , Resorción Ósea/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Síndrome de Coffin-Lowry/genética , Síndrome de Coffin-Lowry/metabolismo , Síndrome de Coffin-Lowry/patología , Colágeno/biosíntesis , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ratones , Ratones Noqueados , Neurofibromina 1/deficiencia , Osteoblastos/patología , Osteoclastos/metabolismo , Osteoclastos/patología , Osteogénesis/genética , Ligando RANK/biosíntesis , Ligando RANK/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/deficiencia , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismoRESUMEN
The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1(ob)(-/-) mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1(ob)(-/-) mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1(ob)(-/-) mice without affecting other organ weight, while a high-protein diet overcame Atf4(-/-) and Rsk2(-/-) mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.