A new regulator of osteoclastogenesis: Estrogen response element–binding protein in bone

The heterogeneous nuclear ribonucleoprotein (hnRNP)–like estrogen response element–binding protein (ERE‐BP) competes with estrogen receptor α (ERα) 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‐κB 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 D3 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 ERα 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‐κB 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. © 2011 American Society for Bone and Mineral Research