The receptor activator of NF-B ligand (RANKL) induces osteoclast differentiation from bone marrow cells in the presence of macrophage colony-stimulating factor. We found that treatment of bone marrow cells with SB203580 inhibited osteoclast differentiation via inhibition of the RANKL-mediated signaling pathway. To elucidate the role of p38 mitogen-activated protein (MAP) kinase pathway in osteoclastogenesis, we employed RAW264 cells which could differentiate into osteoclastlike cells following treatment with RANKL. In a dose-dependent manner, SB203580 but not PD98059, inhibited RANKL-induced differentiation. Among three MAP kinase families tested, this inhibition profile coincided only with the activation of p38 MAP kinase. Expression in RAW264 cells of the dominant negative form of either p38␣ MAP kinase or MAP kinase kinase (MKK) 6 significantly inhibited RANKL-induced differentiation of the cells. These results indicate that activation of the p38 MAP kinase pathway plays an important role in RANKLinduced osteoclast differentiation of precursor bone marrow cells.Bone morphogenesis, remodeling, and resorption are controlled in part by osteoclasts. These cells differentiate from hematopoietic myeloid precursors of monocyte/macrophage lineage under control of osteotropic hormones and local factors produced by supporting cells such as osteoblasts and stromal cells (1-9).The receptor activator of NF-B ligand (RANKL) 1 (10), also refereed to as osteoclast differentiation factor (11), tumor necrosis factor-related activation-induced cytokine (12), or osteoprotegerin ligand (13), was shown to be highly expressed in supporting cells and to directly induce the differentiation and maturation of osteoclasts (7,(13)(14)(15). To describe RANKL-induced osteoclastogenesis, the sequential phenotype progression model was proposed. The model includes the appearance of mononuclear osteoclasts, the fusion process prior to multinucleated osteoclast formation, and the osteoclast maturation process (6). Moreover, it has been shown that mutant mice disrupted with either RANKL or its receptor RANK revealed severe osteopetrosis and osteoclast defects (16,17), indicating that the RANKL-RANK signaling system plays an essential role in osteoclast differentiation.It has been shown recently that RANK is associated with tumor necrosis factor receptor-associated factors (TRAFs) (18 -21). The intracellular domain of RANK contains two distinct TRAF-binding domains, each of which recognizes different TRAF proteins specifically (18,19). While the C-terminal region of RANK interacts with TRAF2 and TRAF5, the TRAF6-binding domain resides in the middle of the RANK intracellular region. Overexpression of RANK C-terminal deletion mutants has revealed that activation of the RANK-mediated signaling pathway results in the activation of NF-B and c-Jun N-terminal kinase (JNK) which correlate with the TRAF6 interaction activity of mutants (18,19). In addition, mice with disrupted TRAF6 gene exhibit an osteopetrotic phenotype due to a defect in bone resorptio...

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

By screening a lambda gt11 library with the multimerized sequence of the cAMP response element (CRE), we isolated human clones encoding the CRE binding protein, CRE‐BP1, from a human brain cDNA library. CRE‐BP1 expressed in Escherichia coli bound not only to the CRE element of the somatostatin and fibronectin genes, but also to the CRE element of the adenovirus E4 gene, suggesting that the protein was not distinguishable from the adenovirus transcription factor, ATF. The human CRE‐BP1 clone encoded a 54.5 kd protein similar at its carboxy terminus to the leucine zipper motifs found in other enhancer binding proteins such as C/EBP and c‐jun/AP‐1. CRE‐BP1 mRNA was expressed in all of the cells examined and was abundant in brain. The structure of CRE‐BP1 and its recognition elements suggest that cellular response to extracellular stimuli is controlled by a family of transcription factors that bind to related cis‐active elements and that contain several highly conserved domains.

Although apoptosis occurs during myogenesis, its mechanism of initiation remains unknown. In a culture model, we demonstrate activation of caspase-12, the initiator of the endoplasmic reticulum (ER) stress-specific caspase cascade, during apoptosis associated with myoblast differentiation. Induction of ER stress-responsive proteins (BiP and CHOP) was also observed in both apoptotic and differentiating cells. ATF6, but not other ER stress sensors, was specifically activated during apoptosis in myoblasts, suggesting that partial but selective activation of ER stress signaling was sufficient for induction of apoptosis. Activation of caspase-12 was also detected in developing muscle of mouse embryos and gradually disappeared later. CHOP was also transiently induced. These results suggest that specific ER stress signaling transmitted by ATF6 leads to naturally occurring apoptosis during muscle development.