Calcitriol suppresses lipopolysaccharide‐induced alveolar bone damage in rats by regulating T helper cell subset polarization

Abstract

Background Although the immunomodulatory properties of calcitriol in bone metabolism have been documented for decades, its therapeutic role in the management of periodontitis remains largely unexplored. In this study, we hypothesized that calcitriol suppresses lipopolysaccharide (LPS)‐induced alveolar bone loss by regulating T helper (Th) cell subset polarization. Methods To test this hypothesis, we determined the effect of calcitriol intervention on the development of LPS‐induced periodontitis in rats in terms of bone loss (micro‐CT analysis), local inflammatory infiltration levels, the number of osteoclasts (hematoxylin and eosin staining) and the level of osteoclastogenesis (tartrate‐resistant acid phosphatase method). Furthermore, immunohistochemistry was used to assess the expression levels of the receptor activator of NF‐κB ligand (RANKL) and osteoprotegerin (OPG) as well as the cytokine levels of interferon‐γ (IFN‐γ), interleukin‐4 (IL‐4), IL‐17, and IL‐10 throughout the LPS‐injected region. Finally, the polarization potential of Th cells in peripheral blood was analyzed using flow cytometry. Results Calcitriol intervention decreased alveolar bone loss in response to LPS injection and inflammatory cell infiltration. Analysis of osteoclast number and RANKL and OPG expression showed that bone resorption activity was largely suppressed in response to calcitriol administration, along with decreased IL‐17 levels but increased IL‐4 and IL‐10 levels in periodontal tissues (the LPS‐injected region). Similarly, the percentages of Th2 and Treg cells in peripheral blood increased, but the percentages of Th1 and Th17 cells decreased in rats receiving calcitriol. Conclusion Our findings suggest that calcitriol can be used to inhibit bone loss in experimental periodontitis, likely via the regulation of local and systemic Th cell polarization.

The therapeutic role of baicalein in combating experimental periodontitis with diabetes via Nrf2 antioxidant signaling pathway

“…Several antioxidant compounds such as resveratrol, paeonol, and isorhamnetin were reported to be able to promote the expression of Nrf2 . A recent study has described an increase in the oxidative damage indicators and a decrease of total Nrf2 in an experiment CPDM model . However, the phosphorylation form of Nrf2 at serine40 has been confirmed to play a key mechanistic role in regulating the resistance to oxidative stress .…”

Determinants of Periodontal/Periapical Lesion Stability and Progression

“…Accordingly, putative Th2 and Tregs products are known for their inhibitory activities on proinflammatory cytokine and RANKL production, as well as the upregulation of OPG, therefore supporting their involvement in lesion inactivity (Araujo-Pires et al 2015; Francisconi et al 2016). Indeed, immunization protocols that result in Th2-polarized response and immunoregulatory strategies that increase Treg activity halted lesion progression (Wang et al 2014; Wilensky et al 2017; Bi, Wang, et al 2019). Furthermore, the adoptive transfer (i.e., transfer of cells originated from another individual with the goal of improving immune functionality; the cells extracted from the donor can be sorted, cultured in vitro, and/or genetically modified for specific subpopulation selection/generation before transfer) of Th2 cells, as well of Tregs, also limits experimental lesion progression (Wang et al 2014; Wilensky et al 2017; Bi, Wang, et al 2019).…”

The relationship between T‐helper cell polarization and the RANKL/OPG ratio in gingival tissues from chronic periodontitis patients

“…During such pathological cascades, many immune cells polarize toward proinflammatory responses; for example, we previously reported increased levels of M1 phenotypes of macrophages in inflammatory gingival tissues (Zhou et al, ). Given the nature of the disease, it is essential to regulate the immune response involved in periodontal reparative events when designing new therapies for periodontitis (e.g., see Bi et al, ; He et al, ; Ni et al, ; Wu et al, ; Yu, Wu, Yin, & Chen, ). Periodontal pathogens also activate T cells, especially CD4+ T cells (T‐helper cells), to develop into various subsets and initiate the acquired immune response (Knight, Liu, Seymour, Faggion, & Cullinan, ; Silva et al, ); subsequently, a spectrum of proinflammatory cytokines are released, which induces tissue damage and bone destruction (Hienz et al, ).…”

“…For example, the Th17 subset causes bone destruction during osteolytic and infectious processes by secreting proinflammatory cytokines, such as IL‐17 and IL‐21 (Bettelli, Korn, & Kuchroo, ; Zhu & Paul, ), whereas Treg cells are useful for bone repair, not only by warding off infection and weakening bacterial virulence but also by diminishing host immune responses, which leads to the incomplete elimination of some foreign agents. Interestingly, the regulation of Th cell polarization either locally or systemically has been demonstrated to inhibit bone loss in experimental periodontitis (Bi et al, ). The involvement of Th17 and Treg subpopulations in periodontal disease makes the inflammatory scenario of periodontitis more complex; unfortunately, the protective or destructive roles of Th17 and Treg cells, in addition to Th1 and Th2 cells, within the overall framework associated with tissue destruction and disease progression remain largely unexplored (Dar, Azam, Anupam, Mondal, & Srivastava, ; Garlet, ).…”

“…Given that the local ratio of receptor activator for nuclear factor‐κB ligand (RANKL) to osteoprotegerin (OPG) in periodontal tissues has been an important hallmark for assessing the degree of bone resorption and the pathological process of periodontitis (Bi et al, ; Bostanci et al, ; Mogi, Otogoto, Ota, & Togari, ), we designed this study to investigate the relationship between inflammation‐related T‐helper cell polarization (e.g., Th1, Th2, Th17, and Treg polarization) and the RANKL/OPG ratio based on gingival crevicular fluid (GCF) and gingival tissues from periodontally healthy (PH) individuals and patients with advanced chronic periodontitis (CP). Our study will provide new clinical evidence concerning the nexus between the immune response and bone destruction during periodontal protective or destructive events.…”