Diabetes is a risk factor for periodontitis, an inflammatory bone disorder and the greatest cause of tooth loss in adults. Diabetes has a significant impact on the gut microbiota, however studies in the oral cavity have been inconclusive. By 16s rRNA sequencing we show here that diabetes causes a shift in oral bacterial composition and, by transfer to germ free mice, that the oral microbiota of diabetic mice is more pathogenic. Furthermore, treatment with IL-17 antibody decreases the pathogenicity of the oral microbiota in diabetic mice; when transferred to recipient germ-free mice oral microbiota from IL-17-treated donors induced reduced neutrophil recruitment, reduced IL-6 and RANKL, and less bone resorption. Thus, diabetes-enhanced IL-17 alters the oral microbiota and renders it more pathogenic. Our findings provide a mechanistic basis to better understand how diabetes can increase the risk and severity of tooth loss.

Diabetes mellitus increases periodontitis and pathogenicity of the oral microbiome. To further understand mechanisms through which diabetes affects periodontitis, we examined its impact on periodontal ligament fibroblasts in vivo and in vitro. Periodontitis was induced by inoculation of Porphyromonas gingivalis and Fusobacterium nucleatum in normoglycemic and diabetic mice. Diabetes, induced by multiple low-dose injections of streptozotocin increased osteoclast numbers and recruitment of neutrophils to the periodontal ligament, which could be accounted for by increased CXC motif chemokine 2 (CXCL2) and receptor activator of nuclear factor kappa B ligand (RANKL) expression by these cells. Diabetes also stimulated a significant increase in nuclear factor kappa B (NF-κB) expression and activation in periodontal ligament (PDL) fibroblasts. Surprisingly, we found that PDL fibroblasts express a 2.3-kb regulatory unit of Col1α1 (collagen type 1, alpha 1) promoter typical of osteoblasts. Diabetes-enhanced CXCL2 and RANKL expression in PDL fibroblasts was rescued in transgenic mice with lineage-specific NF-κB inhibition controlled by this regulatory element. In vitro, high glucose increased NF-κB transcriptional activity, NF-κB nuclear localization, and RANKL expression in PDL fibroblasts, which was reduced by NF-κB inhibition. Thus, diabetes induces changes in PDL fibroblast gene expression that can enhance neutrophil recruitment and bone resorption, which may be explained by high glucose-induced NF-κB activation. Furthermore, PDL fibroblasts express a regulatory element in vivo that is typical of committed osteoblasts.

Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of B139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. European Journal of Human Genetics (2012) 20, 148-154; doi:10.1038/ejhg.2011.167; published online 7 September 2011Keywords: Smith-Magenis syndrome; 17p11.2; RAI1; arrayCGH; mutation; deletion INTRODUCTION Smith-Magenis syndrome (SMS, MIM 182290) is a multiple congenital anomalies and intellectual disability syndrome associated with a deletion of chromosome 17p11. 2. The incidence of SMS is estimated to be B1:15 000-1:25 000 births. 1 SMS is most commonly characterized by a variable degree of intellectual disability including speech and motor delay, craniofacial and skeletal anomalies, sleep disturbance, self-injurious and attention-seeking behaviors. 1,2 Craniofacial features include brachycephaly, midface hypoplasia, tented upper lip, relative prognathism with age and deep-set and hypoteloric eyes. 3,4 Skeletal features include brachydactyly, short stature and short/ broad hands. 3,4 The behavioral phenotype includes onychotillomania, polyembolokoilamania, 'hand licking and page flipping' , 'self-hugging' and hyperactivity. 5 Sleep disturbance is present in 88% of SMS patients and is characterized by difficulty getting to sleep, frequent nocturnal awakenings, early sleep offset and daytime sleepiness with a need for daytime naps. 6,7 SMS clinical features overlap with other intellectual disability syndromes such as Prader-Willi, Williams and Down's syndromes, which often complicate its clinical diagnosis.A majority, B90%, of SMS patients have a deletion of chromosome 17p11.2 that includes the RAI1 gene. 3 The classical SMS deletions span B3.5 Mb of 17p11.2 and are present in B70% of affected individuals.