Regulation of osteoclast differentiation and function by the CaMK-CREB pathway.
Nat Med
; 12(12): 1410-6, 2006 Dec.
Article
em En
| MEDLINE
| ID: mdl-17128269
ABSTRACT
Calcium (Ca(2+)) signaling is essential for a variety of cellular responses and higher biological functions. Ca(2+)/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB) and nuclear factor of activated T cells (NFAT), respectively. The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes. However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members. Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis) that is activated by receptor activator of NF-kappaB ligand (RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoclastos
/
Diferenciação Celular
/
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico
/
Proteínas Quinases Dependentes de Cálcio-Calmodulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article