Eldecalcitol effectively prevents alveolar bone loss by partially improving Th17/Treg cell balance in diabetes-associated periodontitis

Abstract

Background: Diabetes-associated periodontitis (DPD) is an inflammatory and destructive disease of periodontal tissues in the diabetic population. The disease is manifested as more severe periodontal destruction and is more difficult to treat when compared with periodontitis (PD). Eldecalcitol (ELD) is a novel active vitamin D3 analog; however, little clinical evidence is available on its role on improving PD and DPD, and its specific mechanisms remain unclear. In this study, we evaluated the preventative effects of ELD toward PD and DPD and explored its underlying molecular mechanisms.Methods: Experimental PD and DPD mouse models were established by ligation combined with lipopolysaccharide (LPS) from Porphyromonas gingivalis injection in C57BL/6J and C57BLKS/J Iar- + Leprdb/+Leprdb (db/db) mice, respectively. Simultaneously, ELD (0.25 μg/kg) was orally administered to mice via an intragastric method. Micro-computed tomography (CT), hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), and tartrate-resistant acid phosphatase (TRAP) staining were used to evaluate alveolar bone alterations in vivo. Flow cytometry, immunofluorescence, and real-time polymerase chain reaction (qRT-PCR) were also used to examine gene expression and probe systemic and local changes in Treg and Th17 cell numbers. Additionally, western blotting and immunofluorescence staining were used to examine changes in STAT3/STAT5 signaling.Results: Micro-CT and HE staining showed that the DPD group had higher alveolar bone loss when compared with the PD group. After applying ELD, alveolar bone loss decreased significantly in both PD and DPD groups, and particularly evident in the DPD group. IHC and TRAP staining also showed that ELD promoted osteoblast activity while inhibiting the number of osteoclasts, and after ELD treatment, the receptor activator of nuclear factor-κB ligand (RANKL) to osteoprotegerin (OPG) ratio decreased. More importantly, this decreasing trend was more obvious in the DPD group. Flow cytometry and qRT-PCR also showed that the systemic Th17/Treg imbalance in PD and DPD groups was partially resolved when animals were supplemented with ELD, while immunofluorescence staining and qRT-PCR data showed the Th17/Treg imbalance was partially resolved in the alveolar bone of both ELD supplemented groups. Western blotting and immunofluorescence staining showed increased p-STAT5 and decreased p-STAT3 levels after ELD application.Conclusion: ELD exerted preventative effects toward PD and DPD by partially rectifying Th17/Treg cell imbalance via STAT3/STAT5 signaling. More importantly, given the severity of DPD, we found ELD was more advantageous in preventing DPD.

NECA alleviates inflammatory responses in diabetic retinopathy through dendritic cell toll-like receptor signaling pathway

“…Breaking the pro-inflammatory balance between Thl7 and inhibitory Treg cells causes many inflammatory and autoimmune diseases (36). An imbalance between these two cell types can precipitate immune disorders, including ulcerative colitis (UC) (37) and type 2 diabetes mellitus (38). Treg cells are integral in suppressing effector T cells, fostering immune tolerance, and averting autoimmune conditions.…”

“…Conversely, Th17 cells are implicated in various autoimmune diseases. Under normal physiological conditions, these cell types mutually inhibit each other, sustaining a dynamic equilibrium that is vital for immune defense and stability ( 39 ). Th17 cells emerge from DCs within an environment rich in pro-inflammatory cytokines.…”

“…Thl7 and Treg cells are vital in inflammatory response (36)(37)(38)(39). DCs can significantly influence T-cell differentiation (40,41).…”

Halofuginone Inhibits Osteoclastogenesis and Enhances Osteoblastogenesis by Regulating Th17/Treg Cell Balance in Multiple Myeloma Mice with Bone Lesions

“…Th17 cells and IL-17 also play a critical role in the microenvironment of bone marrow in MM patients, as they not only stimulate the growth of myeloma cells, but also break the normal bone balance and accelerate bone destruction by stimulating osteoclasts and inhibiting osteoblasts [ 11 , 12 ]. Treg cells have immunosuppressive functions to prevent excessive damage by the immune system [ 13 ]. They can prevent myeloma cells dissemination, inhibit the stimulation and differentiation of osteoclasts by suppressing RANKL and macrophage colony-stimulating factor (M-CSF), and enhance the proliferation and differentiation of osteoblasts by secreting transforming growth factor (TGF)-β and activating mitogen activated protein kinase (MAPK), leading to an increase in bone mass [ 8 , 14 ].…”

ExploringPorphyromonas gingivalisPathogenesis and Antibody Pool Effect Using a Novel Mouse Reproductive Model

“…P. gingivalis infection is not only responsible for oral periodontal diseases but is also linked to various chronic systemic conditions such as cardiovascular disease (17)(18)(19), Alzheimer's disease (20)(21)(22)(23), diabetes, renal disease, gastrointestinal and respiratory system tumours (24)(25)(26)(27)(28)(29)(30), and adverse pregnancy outcomes (31)(32)(33)(34)(35)(36)(37), including low birth weight and premature births. The connection between local infection and systemic disease has previously been unclear, and experimental results sometimes conflict with proposed hypotheses.…”