A Multivariate Logistic Regression Analysis of Risk Factors for Peri-implant Bone Loss.

OBJECTIVE: To evaluate multiple risk factors of peri-implant bone loss. MATERIALS AND METHODS: A case-control study was conducted on patients who had received dental implants treatment from January 2018 to December 2021. Implants with bone loss were included in the case group, and implants with no bone loss were included in the control group. Risk factors including history of periodontitis, abutment connection type, implant surface, diameter, location, three-dimensional position, opposing dentition, adjacent teeth, prosthetic type, retention type and custom abutment were evaluated. A multivariate logistic regression model was used to evaluate these risk factors, providing corresponding odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 776 implants in 479 patients were included in the analysis. The number of implants in the case group and the control group were 84 and 692, respectively. Cement-retained prostheses (OR=2.439, 95%CI=1.241-4.795) and nonplatform switch design (OR=2.055, 95%CI=1.167-3.619) were identified as weak risk factors. Horizontal deviation (OR=4.177, 95%CI=2.265-7.703) was a moderate risk factor. Vertical deviation (OR=10.107, 95%CI=5.280-19.347) and implants located in the mandibular molar region (OR=10.427, 95%CI=1.176-92.461) were considered high risk factors. CONCLUSION: Implants in the molar region, cement retained, non-platform switch design, and poor three-dimensional implant positioning are identified as significant risk factors for peri-implant bone loss.

Mir155 regulates osteogenesis and bone mass phenotype via targeting S1pr1 gene.

MicroRNA-155 (miR155) is overexpressed in various inflammatory diseases and cancer, in which bone resorption and osteolysis are frequently observed. However, the role of miR155 on osteogenesis and bone mass phenotype is still unknown. Here, we report a low bone mass phenotype in the long bone of Mir155-Tg mice compared with wild-type mice. In contrast, Mir155-KO mice showed a high bone mass phenotype and protective effect against inflammation-induced bone loss. Mir155-KO mice showed robust bone regeneration in the ectopic and orthotopic model, but Mir155-Tg mice showed compromised bone regeneration compared with the wild-type mice. Similarly, the osteogenic differentiation potential of bone marrow stromal stem cells (BMSCs) from Mir155-KO mice was robust and Mir155-Tg was compromised compared with that of wild-type mice. Moreover, Mir155 knockdown in BMSCs from wild-type mice showed higher osteogenic differentiation potential, supporting the results from Mir155-KO mice. TargetScan analysis predicted sphingosine 1-phosphate receptor-1 (S1pr1) as a target gene of Mir155, which was further confirmed by luciferase assay and Mir155 knockdown. S1pr1 overexpression in BMSCs robustly promoted osteogenic differentiation without affecting cell viability and proliferation. Furthermore, osteoclastogenic differentiation of Mir155-Tg bone marrow-derived macrophages was inhibited compared with that of wild-type mice. Thus, Mir155 showed a catabolic effect on osteogenesis and bone mass phenotype via interaction with the S1pr1 gene, suggesting inhibition of Mir155 as a potential strategy for bone regeneration and bone defect healing.

Dicalcium silicate-induced mitochondrial dysfunction and autophagy-mediated macrophagic inflammation promotes osteogenic differentiation of BMSCs.

Dicalcium silicate (Ca2SiO4, C2S) has osteogenic potential but induces macrophagic inflammation. Mitochondrial function plays a vital role in macrophage polarization and macrophagic inflammation. The mitochondrial function of C2S-treated macrophages is still unclear. This study hypothesized: (i) the C2S modulates mitochondrial function and autophagy in macrophages to regulate macrophagic inflammation, and (ii) C2S-induced macrophagic inflammation regulates osteogenesis. We used RAW264.7 cells as a model of macrophage. The C2S (75-150 µg/ml) extract was used to analyze the macrophagic mitochondrial function and macrophage-mediated effect on osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (BMSCs). The results showed that C2S extract (150 µg/ml) induced TNF-α, IL-1ß and IL-6 production in macrophages. C2S extract (150 µg/ml) enhanced reactive oxygen species level and intracellular calcium level but reduced mitochondrial membrane potential and ATP production. TEM images showed reduced mitochondrial abundance and altered the mitochondrial morphology in C2S (150 µg/ml)-treated macrophages. Protein level expression of PINK1, Parkin, Beclin1 and LC3 was upregulated but TOMM20 was downregulated. mRNA sequencing and KEGG analysis showed that C2S-induced differentially expressed mRNAs in macrophages were mainly distributed in the essential signaling pathways involved in mitochondrial function and autophagy. The conditioned medium from C2S-treated macrophage robustly promoted osteogenic differentiation in BMSCs. In conclusion, our results indicate mitochondrial dysfunction and autophagy as the possible mechanism of C2S-induced macrophagic inflammation. The promotion of osteogenic differentiation of BMSCs by the C2S-induced macrophagic inflammation suggests the potential application of C2S in developing immunomodulatory bone grafts.

Rare earth smart nanomaterials for bone tissue engineering and implantology: Advances, challenges, and prospects.

Bone grafts or prosthetic implant designing for clinical application is challenging due to the complexity of integrated physiological processes. The revolutionary advances of nanotechnology in the biomaterial field expedite and endorse the current unresolved complexity in functional bone graft and implant design. Rare earth (RE) materials are emerging biomaterials in tissue engineering due to their unique biocompatibility, fluorescence upconversion, antimicrobial, antioxidants, and anti-inflammatory properties. Researchers have developed various RE smart nano-biomaterials for bone tissue engineering and implantology applications in the past two decades. Furthermore, researchers have explored the molecular mechanisms of RE material-mediated tissue regeneration. Recent advances in biomedical applications of micro or nano-scale RE materials have provided a foundation for developing novel, cost-effective bone tissue engineering strategies. This review attempted to provide an overview of RE nanomaterials' technological innovations in bone tissue engineering and implantology and summarized the osteogenic, angiogenic, immunomodulatory, antioxidant, in vivo bone tissue imaging, and antimicrobial properties of various RE nanomaterials, as well as the molecular mechanisms involved in these biological events. Further, we extend to discuss the challenges and prospects of RE smart nano-biomaterials in the field of bone tissue engineering and implantology.

Sulfonylureas for Treatment of Periodontitis-Diabetes Comorbidity-Related Complications: Killing Two Birds With One Stone.

Periodontitis is one of the most prevalent oral inflammatory diseases leading to teeth loss and oral health problems in adults. Periodontitis mainly affects periodontal tissue by affecting the host immune system and bone homeostasis. Moreover, periodontitis is associated with various systemic diseases. Diabetes is a metabolic disease with systemic effects. Both periodontitis and diabetes are common inflammatory diseases, and comorbidity of two diseases is linked to exacerbation of the pathophysiology of both diseases. Since bacterial dysbiosis is mainly responsible for periodontitis, antibiotics are widely used drugs to treat periodontitis in clinics. However, the outcomes of antibiotic treatments in periodontitis are not satisfactory. Therefore, the application of anti-inflammatory drugs in combination with antibiotics could be a treatment option for periodontitis-diabetes comorbidity. Anti-diabetic drugs usually have anti-inflammatory properties and have shown beneficial effects on periodontitis. Sulfonylureas, insulin secretagogues, are the earliest and most widely used oral hypoglycemic drugs used for type-2 diabetes. Studies have found that sulfonylurea drugs can play a certain role in the mitigation of periodontitis and inflammation. This article reviews the effects of sulfonylurea drugs on the mitigation of periodontitis-diabetes comorbidity-related inflammation, bone loss, and vascular growth as well as the involved molecular mechanisms. We discuss the possibility of a new application of sulfonylureas (old drug) to treat periodontitis-diabetes comorbidity.

The Emerging Role of Exosomes in Oral Squamous Cell Carcinoma.

Oral cancer constitutes approximately 2% of all cancers, while the most common type, oral squamous cell carcinoma (OSCC) represents 90% of oral cancers. Although the treatment of OSCC has improved recently, it still has a high rate of local recurrence and poor prognosis, with a 5-year survival rate of only 50%. Advanced stage OSCC tends to metastasize to lymph nodes. Thus, exploring new therapeutic strategies for OSCC is therefore an urgent priority. Exosomes, the small membrane vesicles derived from endosomes, have been detected in a wide array of bodily fluids. Exosomes contain a diversity of proteins, mRNAs, and non-coding RNAs, including microRNAs, long non-coding RNAs, piRNAs, circular RNAs, tsRNAs, and ribosomal RNAs, which are delivered to neighboring cells or even transported to distant sites. Exosomes have been associated with the tumorigenesis of OSCC, promote the proliferation, colonization, and metastasis of OSCC by transferring their contents to the target cells. Furthermore, exosomes are involved in the regulation of the tumor microenvironment to transform conditions favoring cancer progression in vivo. In this review, we summarize the crucial role of exosomes in the tumorigenesis and progression of OSCC and discuss the potential clinical application of exosomes in OSCC treatment.

Downregulation of Macrophage-Specific Act-1 Intensifies Periodontitis and Alveolar Bone Loss Possibly via TNF/NF-κB Signaling.

Periodontitis is a chronic inflammatory oral disease that affects almost half of the adult population. NF-κB activator 1 (Act1) is mainly expressed in immune cells, including macrophages, and modulates immune cells' function to regulate inflammation in inflammatory diseases. Macrophages play a vital role in the pathophysiology of periodontitis. However, the effect of macrophage-specific Act1 on periodontitis has not been investigated yet. This study aims to unravel the role of macrophage-specific Act1 on the pathophysiology of periodontitis. The expression of Act1 in healthy and periodontitis periodontal tissue was confirmed by immunohistochemistry. Macrophage-specific Act1 expression downregulated (anti-Act1) mice were developed by inserting anti-Act1 antisense oligonucleotides after the CD68 promoter of C57BL/6 mice. Ligature-induced periodontitis (LIP) was induced in anti-Act1 mice and wildtype mice. Micro-CT, histology, and TRAP staining analyzed the periodontal tissue status, alveolar bone loss, and osteoclast numbers. Immunohistochemistry, RT-qPCR, and ELISA analyzed the inflammatory cells infiltration, expression of inflammatory cytokines, and M1/M2 macrophage polarization. mRNA sequencing of in vitro bacterial lipopolysaccharide (LPS)-treated peritoneal macrophages analyzed the differentially expressed genes in anti-Act1 mice during inflammation. Anti-Act1 mice showed aggravated periodontitis and alveolar bone loss compared to wildtype. Periodontitis-affected periodontal tissue (PAPT) of anti-Act1 mice showed a higher degree of macrophage infiltration, and M1 macrophage polarization compared to wildtype. Levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNFα), and macrophage activity-related factors (CCL2, CCL3, and CCL4) were robustly high in PAPT of anti-Act1 mice compared to wildtype. mRNA sequencing and KEGG analysis showed activated TNF/NF-κB signaling in LPS-treated macrophages from anti-Act1 mice. In vitro studies on LPS-treated peritoneal macrophages from anti-act1 mice showed a higher degree of cell migration and expression of inflammatory cytokines, macrophage activity-related factors, M1 macrophage-related factors, and TNF/NF-κB signaling related P-p65 protein. In conclusion, downregulation of macrophage-specific Act1 aggravated periodontitis, alveolar bone loss, macrophage infiltration, inflammation, and M1 macrophage polarization. Furthermore, LPS-treated macrophages from anti-Act1 mice activated TNF/NF-κB signaling. These results indicate the distinct role of macrophage-specific Act1 on the pathophysiology of periodontitis possibly via TNF/NF-κB signaling.