Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus

BACKGROUND: IL-10 has a potent inhibitory effect on osteoclastogenesis. In vitro and in vivo studies confirm the importance of this cytokine in bone metabolism, for instance IL-10-deficient mice develop the hallmarks of osteoporosis. Although it is known that IL-10 directly inhibits osteoclastogenesis at an early stage, preventing differentiation of osteoclast progenitors to preosteoclasts, the precise mechanism of its action is not yet clear. Several major pathways regulate osteoclastogenesis, with key signalling genes such as p38, TRAF6, NF-κB and NFATc1 well established as playing vital roles. We have looked at gene expression in eleven of these genes using real-time quantitative PCR on RNA extracted from RANKL-treated RAW264.7 monocytes. RESULTS: There was no downregulation by IL-10 of DAP12, FcγRIIB, c-jun, RANK, TRAF6, p38, NF-κB, Gab2, Pim-1, or c-Fos at the mRNA level. However, we found that IL-10 significantly reduces RANKL-induced NFATc1 expression. NFATc1 is transcribed from two alternative promoters in Mus musculus and, interestingly, only the variant transcribed from promoter P1 and beginning with exon 1 was downregulated by IL-10 (isoform 1). In addition, immunofluorescence studies showed that IL-10 reduces NFATc1 levels in RANKL-treated precursors and suppresses nuclear translocation. The inhibitory effect of IL-10 on tartrate-resistant acid phosphatase-positive cell number and NFATc1 mRNA expression was reversed by the protein kinase C agonist phorbol myristate acetate, providing evidence that interleukin-10 disrupts NFATc1 activity through its effect on Ca(2+ )mobilisation. CONCLUSION: IL-10 acts directly on mononuclear precursors to inhibit NFATc1 expression and nuclear translocation, and we provide evidence that the mechanism may involve disruption of Ca(2+ )mobilisation. We detected downregulation only of the NFATc1 isoform 1 transcribed from promoter P1. This is the first report indicating that one of the ways in which IL-10 directly inhibits osteoclastogenesis is by suppressing NFATc1 activity

Predictors of long-term stability of maxillary dental arch dimensions in patients treated with a transpalatal arch followed by fixed appliances

Background: The aim of this retrospective study was to identify which dental and/or cephalometric variables were predictors of long-term maxillary dental arch stability in patients treated with a transpalatal arch (TPA) during the mixed dentition phase followed by full fixed appliances in the permanent dentition. Methods: Thirty-six patients, treated with TPA followed up by full fixed appliances, were divided into stable and relapse groups based on the long-term presence or not of relapse. Intercuspid, interpremolar and intermolar widths, arch length and perimeter, crowding, and upper incisor proclination were evaluated before treatment (T0), post-TPA treatment (T1), post-fixed appliance treatment (T2), and a minimum of 3 years after full fixed appliances’ removal (T3). A binary logistic regression was performed thereafter to evaluate the impact of the dental arch and cephalometric measurements at T1 and the changes between T0 and T1 as predictive variables for relapse at T3. Results: The proposed model explained 42.7 % of the variance in treatment stability and correctly classified 72.2 % of the sample. Of the seven predictive variables, only upper anterior crowding (p = 0.029) was statistically significant. For every millimeter of decreased crowding at T1 (after TPA treatment/before starting the fixed orthodontic treatment), there was an increase of 3.57 times in the odds of having stability. Conclusions: The best predictor of relapse was maxillary crowding before treatment. The odds of relapse increase by 3.6 times for every millimeter of crowding at baseline