Periodontitis is one of the most common oral diseases resulting in gingival inflammation and tooth loss. Growing evidence indicates that it results from dysbiosis of the oral microbiome, which interferes with the host immune system, leading to bone destruction. Immune cells activate periodontal ligament cells to express the receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) and promote osteoclast activity. Osteocytes have active roles in periodontitis progression in the bone matrix. Local proteins are involved in bone regeneration through functional immunological plasticity. Here, we discuss the current knowledge of cellular and molecular mechanisms in periodontitis, the roles of local proteins, and promising synthetic compounds generating a periodontal regeneration effect. It is anticipated that this may lead to a better perception of periodontitis pathophysiology.

Macrolide antibiotics exert antiinflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using 2 distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the antiinflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein developmental endothelial locus-1 (DEL-1). Consistent with the anti–neutrophil recruitment action of endothelial cell–derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1–dependent manner. Whereas ERM (but not other antibiotics, such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Del1 -deficient mice. By interacting with the growth hormone secretagogue receptor and activating JAK2 in human lung microvascular endothelial cells, ERM induced DEL-1 transcription that was mediated by MAPK p38 and was CCAAT/enhancer binding protein–β dependent. Moreover, ERM reversed IL-17–induced inhibition of DEL-1 transcription, in a manner that was dependent not only on JAK2 but also on PI3K/AKT signaling. Because DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may lead to a novel approach for the treatment of inflammatory and aging-related diseases.

The periodontal Ruffini ending has been reported to show immunoreactivity for tyrosine kinase B (trkB), the high‐affinity receptor for brain‐derived neurotrophic factor (BDNF), in the periodontal ligament of the rat incisor. Furthermore, adult heterozygous BDNF‐mutant mice showed malformation and reduction of the periodontal Ruffini endings. To investigate further roles of BDNF in these structures, the development, distribution, and terminal morphology of Ruffini endings were examined in the incisor periodontal ligament of heterozygous and homozygous BDNF mutant mice, as well as in the wild‐type littermate by immunohistochemistry for protein gene product (PGP) 9.5, a general neuronal marker. A similar distribution and terminal formation of PGP 9.5‐immunoreactive nerve fibers was recognized in the periodontal ligament of all phenotypes at postnatal week (PW) 1. At this stage, the nerve fibers had a beaded appearance, but did not form the periodontal Ruffini endings. At PW2, the heterozygous and wild‐type mice started to show ramified nerve fibers resembling the mature shape of periodontal Ruffini endings. At PW3, the Ruffini endings occurred in the periodontal ligament of the wild‐type and heterozygous mice. While the Ruffini endings of the wild‐type mice appeared either ruffled or smooth, as reported previously, most of these structures showed a smooth outline in the heterozygous mice. The homozygous mice lacked the typical Ruffini endings at PW3. In the quantitative analysis, homozygous mice had the smallest percentages of PGP 9.5‐immunoreactive areas at the same postnatal periods, but there were no significant differences between wild‐type and heterozygous mice during PW1–3. These findings suggest a possible involvement of BDNF during the postnatal development and, in particular, the maturation of periodontal Ruffini endings. Furthermore, other neurotrophins may play a role in the development and/or early maturation of the periodontal nerve fibers, as indicated by the presence of nerve fibers in the BDNF‐homozygous mice. Anat Rec Part A 274A:807–816, 2003.

Epithelial sodium channels (ENaCs) are a subfamily of ion channels within the degenerin/ENaC (DEG/ENaC) superfamily. Previous studies have shown the immunolocalization of ENaC in the neural elements of the Cutaneous mechanoreceptors as well as dorsal root and trigeminal ganglion neurons, indicating the involvement of this molecule in mechanotransduction. The present study examined the expression of ENaC beta, a major component of ENaC protein, in the mechanoreceptive Ruffini endings in the periodontal ligament of the rat incisors by immunohistochemistry. The expression of ENaC beta in the trigeminal ganglion-which innervates the periodontal Ruffini endings-was also investigated at the mRNA and protein levels. Furthermore, double staining and a nerve injury experiment were applied to clarify its detailed localization in the periodontal Ruffini endings. ENaC beta immunoreaction in the trigeminal ganglion was recognizable in the comparatively large neurons which have been considered to mediate mechanotransduction. Immunohistochemistry for ENaC beta demonstrated dendritic ramifications of the Ruffini endings as well as the rounded cells in the periodontal ligament. Double staining with ENaC beta and either PGP9.5 or S-100 protein showed immunoreaction for ENaC beta in both the axonal and glial elements in the periodontal ligament. Some ENaC beta positive cells with rounded profiles were reactive to non-specific cholinesterase activity. Furthermore, a transection of the inferior alveolar nerve failed to eliminate the rounded cells with ENaC beta reaction, indicating that they were the terminal Schwann cells associated with the periodontal Ruffini endings. These findings suggest that ENaC beta is a key mechanotransducing channel in the periodontal Ruffini endings. Probably, the terminal Schwann cells together with the axon terminals regulate mechanotransduction in the periodontal endings.

Hyperammonemia is known to cause various neurological dysfunctions such as seizures and cognitive impairment. Several studies have suggested that hyperammonemia may also be linked to the development of Alzheimer’s disease (AD). However, the direct evidence for a role of ammonia in the pathophysiology of AD remains to be discovered. Herein, we report that hyperammonemia increases the amount of mature amyloid precursor protein (mAPP) in astrocytes, the largest and most prevalent type of glial cells in the central nervous system that are capable of metabolizing glutamate and ammonia, and promotes amyloid beta (Aβ) production. We demonstrate the accumulation of mAPP in astrocytes was primarily due to enhanced endocytosis of mAPP from the plasma membrane. A large proportion of internalized mAPP was targeted not to the lysosome, but to the endoplasmic reticulum, where processing enzymes β-secretase BACE1 (beta-site APP cleaving enzyme 1) and γ-secretase presenilin-1 are expressed, and mAPP is cleaved to produce Aβ. Finally, we show the ammonia-induced production of Aβ in astrocytic endoplasmic reticulum was specific to Aβ42, a principal component of senile plaques in AD patients. Our studies uncover a novel mechanism of Aβ42 production in astrocytes and also provide the first evidence that ammonia induces the pathogenesis of AD by regulating astrocyte function.

The macrolide erythromycin (ERM) inhibits excessive neutrophil accumulation and bone resorption in inflammatory tissues. We previously reported that the expression of developmental endothelial locus-1 (DEL-1), an endogenous anti-inflammatory factor induced by ERM, is involved in ERM action. Furthermore, DEL-1 is involved in the induction of bone regeneration. Therefore, in this study, we investigated whether ERM exerts an osteoblastogenic effect by upregulating DEL-1 under inflammatory conditions. We performed in vitro cell-based mechanistic analyses and used a model of Porphyromonas gingivalis lipopolysaccharide (LPS)-induced periodontitis to evaluate how ERM restores osteoblast activity. In vitro, P. gingivalis LPS stimulation suppressed osteoblast differentiation and bone formation. However, ERM treatment combined with P. gingivalis LPS stimulation upregulated osteoblast differentiation-related factors and Del1, indicating that osteoblast differentiation was restored. Alveolar bone resorption and gene expression were evaluated in a periodontitis model, and the results confirmed that ERM treatment increased DEL-1 expression and suppressed bone loss by increasing the expression of osteoblast-associated factors. In conclusion, ERM restores bone metabolism homeostasis in inflammatory environments possibly via the induction of DEL-1.