International Journal of Oral Science最新文献

Rheumatoid arthritis (RA) is an autoimmune disorder that triggers progressive joint destruction by inducing excessive osteoclastogenesis. Porphyromonas gingivalis (Pg), the main pathogenic bacterium involved in periodontitis (PD), is closely related to RA. Pg can secrete extracellular vesicles (EVs), which carry numerous virulence factors. The aim of this study was to investigate whether Pg-derived EVs can be transported and exacerbate bone destruction in RA by promoting osteoclastogenesis and to elucidate the underlying mechanisms involved. EVs derived from Porphyromonas endodontalis (Pe), which is weakly associated with PD or RA, were used as controls. Pg and Pe EVs interact with osteoclasts after translocating into the marrow and metacarpal joints of mice. In vitro, Pg EVs induce osteoclastogenesis via various components, such as lipopolysaccharide, proteins, lipoproteins, and proteases. TNF-α, IL-1β, and IL-6 promote but cannot independently control Pg EV-induced osteoclastogenesis. RNA sequencing and verification experiments further demonstrated that Pg EVs induced osteoclastogenesis by promoting the phosphorylation of spleen tyrosine kinase (Syk). In vivo, Pg EVs exacerbated RA-induced bone destruction by activating Syk-dependent osteoclastogenesis. R406, a Syk inhibitor, significantly attenuated Pg EV-induced RA osteoclastogenesis and bone destruction. However, Pe-derived EVs presented an extremely weak ability to promote osteoclastogenesis and RA. Our findings reveal a new mechanism by which Pg EVs can exacerbate RA via transport through the circulation and the promote Syk-dependent osteoclastogenesis. This study deepens our understanding of the significant pathogenic role of EVs derived from oral bacterial in RA and explores targeted therapeutic strategies by inhibiting the activation of Syk.

Temporomandibular joint osteoarthritis (TMJ-OA) affects a significant proportion of the population worldwide. However, there has been no substantial progress in the development of FDA-approved drugs for treatment due to a lack of understanding of the specific factors regulating key TMJ-OA molecular mechanisms. Lysyl Oxidase-Like-2 (LOXL2) promotes knee joint cartilage protection and is downregulated in a TMJ-OA animal model. We evaluated the role of LOXL2 in TMJ cartilage, its molecular mechanism, and gene networks using in vivo Loxl2 knockout mice (Acan-Cre; Loxl2^flox/flox) and ex vivo goat TMJ cartilage. Our results show that Loxl2 knockout in mouse cartilage upregulates Il1b, Mmp9, Mmp13, Adamts4, and Adamts5, but reduces the levels of aggrecan and proteoglycan. Loxl2 deleted TMJ cartilage show a higher enrichment of inflammatory response, TNFA signaling via NF-κB, extracellular matrix (ECM), and collagen degradation pathway network. Conversely, LOXL2 treatment reduces interleukin-1 beta (IL-1β)-induced expression of Mmp13, protects mitochondrial function, and ECM from degeneration. Importantly, LOXL2 attenuates IL-1β-induced chondrocyte apoptosis via the phosphorylation of NF-κB and expression of the pain-related gene PTGS2 (encodes COX2). Taken together, Loxl2 knockout mice exacerbate TMJ-OA through cartilage/ECM degradation, mitochondrial dysfunction, chondrocyte apoptosis, and inflammatory gene expression, whereas LOXL2 treatment mitigate these effects.

Enamel, the inorganic tissue covering the crowns of teeth, is known for its remarkable resilience and hardness. These properties originate from its high proportion of mineralized matrix and complex internal microarchitecture. On an ultrastructural level, it consists of directionally arranged enamel prisms. Continuously growing rodent incisors are an exemplary case of this phenomenon. Their enamel has a consistent decussation pattern, providing teeth with extremely high resistance and ensuring they remain constantly sharp. While the decussation pattern has been described in detail, mechanisms behind its formation have not been experimentally proven. Here, we show that the highly organized enamel micropattern is generated by directional epithelial sliding of enamel-forming ameloblasts in vivo. Our results detail how enamel micropatterning stems from individual cell cluster segregation and subsequent reciprocal interweaving. Based on this determination, we introduce and experimentally demonstrate a new model of enamel decussation pattern formation.

Copper, predominantly present in bones, plays a crucial role in bone formation. However, when copper homeostasis is disrupted, excessive copper can trigger harmful inflammation and a novel form of cell death known as cuproptosis. The impact of cuproptosis on bone metabolism remains unclear. In this study, we demonstrated that excessive copper acts as an aggravator in osteoclastogenesis and bone resorption. We observed that the expression levels of the copper importer SLC31A1 and dihydrolipoamide S-acetyltransferase (DLAT) were positively correlated with bone loss in both human chronic apical periodontitis (CAP) tissues and mouse CAP models. Untargeted metabolomics analysis and screening of glucose metabolism enzymes revealed that glycogen synthesis was inhibited during cuproptosis. Mechanistically, excessive copper hindered glycogen synthesis via glycogen synthase 1 (GYS1), which limited the availability of glycogenolysis-derived glucose-6-phosphate (G6P) flux into pentose phosphate pathway (PPP), and was unable to yield abundant NADPH to ensure high demand of glutathione (GSH) for macrophage survival. The inhibition of glycogen synthesis intensified cuproptosis and bone-resorption activity. Moreover, excessive copper bound to H3K27me3, which further epigenetically inhibited the gene transcription of GYS1, thereby affecting glycogen synthesis and exacerbating cuproptosis and bone resorption. Furthermore, the disruption of glycogen metabolism intensified cuproptosis and promoted inflammatory bone loss in vivo. Our finding highlighted the complex interplay among copper homeostasis, glycogen metabolism, and the osteo-immune system, suggesting new therapeutic strategies for managing inflammatory bone diseases and other copper accumulation-related conditions through the metabolic reprogramming of cells.

Epidemiological studies have highlighted an association between periodontitis and osteoporosis. However, the mechanism underlining this association remains unclear. Here, we revealed significant differences in the salivary microbiota between periodontally healthy individuals and periodontitis patients, with periodontitis patients exhibiting increased salivary microbiota diversity and an elevated abundance of pathogenic bacteria. Using an ovariectomized (OVX) mouse model, we demonstrated that the salivary microbiota from periodontitis patients exacerbated bone destruction by modulating the gut microbiota. Metabolomic analysis revealed that the periodontitis-associated salivary microbiota suppressed tryptophan metabolism. The tryptophan metabolite indole-3-lactic acid (ILA) directly inhibited osteoclast formation and differentiation. In OVX mice treated with periodontitis salivary microbiota, supplementation with ILA effectively suppressed osteoclastogenesis and alleviated the detrimental effects of periodontitis-associated salivary microbiota on systemic bones. In summary, our data demonstrate that periodontitis can affect systemic bone metabolism via the oral-gut axis and that ILA supplementation serves as a potential therapeutic option to mitigate these adverse effects.

Tooth developmental anomalies are a group of disorders caused by unfavorable factors affecting the tooth development process, resulting in abnormalities in tooth number, structure, and morphology. These anomalies typically manifest during childhood, impairing dental function, maxillofacial development, and facial aesthetics, while also potentially impacting overall physical and mental health. The complex etiology and diverse clinical phenotypes of these anomalies pose significant challenges for prevention, early diagnosis, and treatment. As they usually emerge early in life, long-term management and multidisciplinary collaboration in dental care are essential. However, there is currently a lack of systematic clinical guidelines for the diagnosis and treatment of these conditions, adding to the difficulties in clinical practice. In response to this need, this expert consensus summarizes the classifications, etiology, typical clinical manifestations, and diagnostic criteria of tooth developmental anomalies based on current clinical evidence. It also provides prevention strategies and stage-specific clinical management recommendations to guide clinicians in diagnosis and treatment, promoting early intervention and standardized care for these anomalies.