BackgroundPeriodontitis is an inflammatory disease of the tissues surrounding teeth that causes destruction of connective tissues. During the progress of periodontitis, osteoclasts are solely accountable for the resorption of alveolar bones that leads to the loss of teeth if not properly treated. Thus, the development of effective anti‐resorptive therapies will greatly benefit the treatment of periodontitis patients. In the present study, we suggest an inhibitory effect of 6‐shogaol, an ingredient of ginger, on osteoclast differentiation and bone resorption.MethodsMouse bone marrow cells were cultured in the presence of macrophage‐colony stimulating factor and receptor activator of nuclear factor‐κB ligand (RANKL) to investigate the effect of 6‐shogaol on osteoclast differentiation and intracellular signaling pathways. 6‐shogaol significantly reduced osteoclast differentiation, actin ring formation, and resorption. In the presence of 6‐shogaol, osteoclast signaling including the RANKL‐induced activation of mitogen‐activated protein kinases, Ca2+ oscillation, generation of reactive oxygen species, and nuclear factor of activated T‐cells, cytoplasmic 1 nuclear translocation was significantly inhibited in vitro. Furthermore, a ligature‐induced periodontitis model in mice was used to determine the role of 6‐shogaol in vivo.ResultsThe administration of 6‐shogaol prevented osteoclastogenesis and alveolar bone resorption induced by ligature. Furthermore, the ligature‐induced number of macrophages and neutrophils as well as the expression of interleukin‐1β and tumor necrosis factor‐α were considerably lower in the periodontal tissues following shogaol injection.ConclusionThese results confirm the anti‐osteoclastogenic effect of 6‐shogaol and suggest the possibility of application as an anti‐resorptive strategy in periodontitis.
Combined, these results suggest fluvastatin directly inhibited osteoclastogenesis and efficiently blocked bone erosion.
Background Periodontitis is not only one of the most prevalent inflammatory diseases among adults, but also commonly linked to numerous systemic conditions including cardiovascular diseases, stroke, and diabetes. Although osteoclasts are responsible for the alveolar bone resorption during periodontitis pathogenesis, the development of pharmacologic strategies targeting these cells has not been vastly fruitful. Methods Bone marrow macrophages were cultured in the presence of macrophage‐colony stimulating factor (M‐CSF) and receptor activator of nuclear factor κB ligand (RANKL) to examine the direct effect of acalabrutinib on osteoclastogenesis. Ca2+ oscillation and nuclear localization of NFATc1 in osteoclast precursors were examined to determine the precise molecular mechanism. LPS‐induced alveolar bone loss model was employed for studying effect in in vivo bone resorption. Results Acalabrutinib directly inhibited RANKL and LPS‐induced in vitro osteoclast differentiation. In addition, acalabrutinib inhibited RANKL‐induced phosphorylation of mitogen‐activated protein kinases and reduced the expression of NF‐κB. The inhibitory mechanism involved suppression of Ca2+ oscillation in osteoclast precursors resulting in the decreased NFATc1 expression and nuclear localization, which is a crucial prerequisite for osteoclastogenesis. The administration of acalabrutinib significantly reduced P. gingivalis lipopolysaccharide‐induced alveolar bone erosion in mice. Conclusion These data indicate that acalabrutinib is an effective inhibitor of osteoclastogenesis both in vitro and in vivo, with a potential for a novel strategy against bone destruction by periodontitis.
FUSE binding protein 1 (Fubp1), a regulator of the c-Myc transcription factor and a DNA/RNA-binding protein, plays important roles in the regulation of gene transcription and cellular physiology. In this study, to reveal the precise developmental function of Fubp1, we examined the detailed expression pattern and developmental function of Fubp1 during tooth morphogenesis by RT-qPCR, in situ hybridization, and knock-down study using in vitro organ cultivation methods. In embryogenesis, Fubp1 is obviously expressed in the enamel organ and condensed mesenchyme, known to be important for proper tooth formation. Knocking down Fubp1 at E14 for two days, showed the altered expression patterns of tooth development related signalling molecules, including Bmps and Fgf4. In addition, transient knock-down of Fubp1 at E14 revealed changes in the localization patterns of c-Myc and cell proliferation in epithelium and mesenchyme, related with altered tooth morphogenesis. These results also showed the decreased amelogenin and dentin sialophosphoprotein expressions and disrupted enamel rod and interrod formation in one- and three-week renal transplanted teeth respectively. Thus, our results suggested that Fubp1 plays a modulating role during dentinogenesis and amelogenesis by regulating the expression pattern of signalling molecules to achieve the proper structural formation of hard tissue matrices and crown morphogenesis in mice molar development.
NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly lower leptin with age. We challenged young mice with a high fat diet finding that cKO mice gained less weight and showed improved glucose metabolism. Low levels of recombination at the IKKα locus were detected in fat pads isolated from old cKO mice. To determine whether recombination occurs in adipocytes, we examined fat pads in Osx-Cre;TdT reporter mice; these showed increasing Osx-Cre-mediated expression in peripheral adipocytes from 6 weeks to 18 months. Since Osx-Cre drives recombination in peripheral adipocytes with age, we conclude that fat loss in cKO mice is most likely caused by progressive deficits of IKKα in adipocytes.
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