A New Regulator of Osteoclastogenesis: Estrogen Response Element-Binding Protein in Bone

作者：Chen Hong; Gilbert Linda C; Lu X; Liu Zhaofan; You Shaojin; Weitzmann M Neale; Nanes Mark S^*; Adams John

来源：Journal of Bone and Mineral Research, 2011, 26(10): 2537-2547.

DOI：10.1002/jbmr.456

• OSTEOCLAST
• ESTROGEN
• hnRNP
• RANKL
• OSTEOCLASTOGENESIS
• BONE

The heterogeneous nuclear ribonucleoprotein (hnRNP)-like estrogen response element-binding protein (ERE-BP) competes with estrogen receptor alpha (ER alpha) for occupancy of estrogen response elements (EREs). Here we report that ERE-BP potently stimulates osteoclastogenesis. ERE-BP mRNA and protein were found to be expressed ubiquitously in bone. Overexpression of ERE-BP in cultured osteoblasts stimulated expression of the receptor activator of NF-kappa B ligand (RANKL) and decreased osteoprotegerin (OPG). The effect of ERE-BP on RANKL was shown to be transcriptional in transient transfection assay and competed with via the ER. Constitutive expression of ERE-BP increased the sensitivity of cells toward 1,25-dihydroxyvitamin D(3) stimulation of RANKL expression. In contrast, knockdown of ERE-BP in stromal ST-2 cells decreased basal RANKL promoter activity. Cocultures of ERE-BP lentivirus-transduced ST-2 cells with spleen monocytes induced formation of multinucleated osteoclasts (OCs) characterized by tartrate-resistant acid phosphatase, calcitonin receptors, and functional calcium resorption from bone slices. Although ER alpha competed with ERE-BP for an ERE in a dose-dependent manner, ERE-BP was an independent and potent regulator of RANKL and osteoclastogenesis. In preosteoclastic RAW cells, overexpression of ERE-BP increased RANK, upregulated NF-kappa B signaling, and enhanced differentiation toward a mature OC phenotype independent of RANKL. These results identify ERE-BP as a potent modulator of osteoclastogenesis. We hypothesize that ERE-BP may play a critical role in the regulation of bone homeostasis as a modulator of estrogen sensitivity as well as by direct action on the transcription of critical osteoclastogenic genes.

• 出版日期2011-10
• 单位UCLA