Inhibition of osteoblastic bone formation by nuclear factor-kappaB

Inhibition of osteoblastic bone formation by nuclear factor-kappaB. This repressed the NF-B-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-B/NFATc1 axis plays a pivotal role in bone remodeling and represents a therapeutic target for bone diseases. INTRODUCTION Interferon-related developmental regulator 1 (Ifrd1) is a transcriptional coactivator/repressor that controls gene expression by interacting with transcription factors or histone deacetylase (HDAC) complexes. Ifrd1 expression is upregulated by acute tissue injuries, including cerebral ischemia/reperfusion and muscle trauma (1). It is also upregulated by various growth factors and cytokines (2). Ifrd1 is implicated in the pathophysiology of cystic fibrosis through regulation of the function of neutrophil effector cells (3). In addition, Ifrd1 is a candidate gene for autosomal-dominant sensory/motor neuropathy with ataxia (4). In summary, Ifrd1 has been implicated in the regulation of cell growth and differentiation, in addition to the pathogenesis of various Triclosan diseases, by modulating gene expression patterns. Bone-forming osteoblasts and bone-resorbing osteoclasts regulate the integrity of the skeleton in a sophisticated fashion (5, 6). The osteoblast lineage is derived from primitive multipotent mesenchymal stem cells with the potential to differentiate into bone marrow stromal cells, chondrocytes, Triclosan muscles, and adipocytes (7). Osteoclasts are multinucleated cells derived from hematopoietic stem cells and share the same lineage as macrophages Triclosan and dendritic cells (8). The modulation of bone remodeling and bone homeostasis is tightly regulated by three essential mechanisms. These are the cell-autonomous regulation of osteoblastogenesis, the cell-autonomous regulation of osteoclastogenesis, and the osteoblast-dependent regulation of osteoclastogenesis (9). Recently, we demonstrated that Ifrd1 expression in osteoblasts represses osteoblastogenesis and activates osteoclastogenesis by modulating the nuclear factor B (NF-B)/Smad/Osterix and -catenin/osteoprotegerin (OPG) pathways, respectively (10). These results Triclosan indicate that Ifrd1 expression in osteoblasts regulates bone homeostasis by modulating the cell-autonomous regulation of osteoblastogenesis (bone formation) and the osteoblast-dependent regulation of osteoclastogenesis (bone resorption). To further establish the pivotal role of Ifrd1 in bone homeostasis, we generated osteoclast-specific and mice (10) were crossed with either (11), ((12), or mice (13). These mutant mice were backcrossed more than five generations with C57BL/6J mice. Mice were bred under standard animal housing conditions at 23 1C with humidity of 55% and a light/dark cycle of 12 h, with SPRY1 free access to food and water. Genotyping was performed by PCR using tail genomic DNA. The study protocol meets the guidelines of the Japanese Pharmacological Society and was approved by the Committee for the Ethical Use of Experimental Animals at Kanazawa University, Kanazawa, Japan. The numbers of animals used per experiment are stated in the figure legends. Bone histomorphometric analyses and CT analyses. Bone histomorphometric analyses were performed on vertebrae as previously described (14). Briefly, the vertebrae were fixed with 10% formalin, followed by dehydration in different concentrations of ethanol and subsequent embedding in methyl methacrylate resin according to standard protocols. The ratio of bone volume to tissue volume (BV/TV), one of the trabecular bone structural parameters, was measured by von Kossa staining, which detects calcium deposits in tissue. Bone formation rate (BFR), which is the calculated rate at which cancellous bone surface and bone volume are being replaced annually, was analyzed by the calcein double-labeling method. Calcein was injected into mice twice with an interval of 3 days, and the mice were sacrificed 2 days after the last injection. Osteoblast and osteoclast parameters were analyzed by staining with toluidine blue or tartrate-resistant acid phosphatase (TRAP), respectively. Analyses were performed using the OsteoMeasure analysis system (OsteoMetrics, Inc., Atlanta, GA) according.

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