Tristetraprolin Is Required for Alveolar Bone Homeostasis

Abstract

Tristetraprolin (TTP) is an RNA-binding protein that targets numerous immunomodulatory mRNA transcripts for degradation. Many TTP targets are key players in the pathogenesis of periodontal bone loss, including tumor necrosis factor-α. To better understand the extent that host immune factors play during periodontal bone loss, we assessed alveolar bone levels, inflammation and osteoclast activity in periodontal tissues, and immune response in draining cervical lymph nodes in TTP-deficient and wild-type (WT) mice in an aging study. WT and TTP-deficient (knockout [KO]) mice were used for all studies under specific pathogen-free conditions. Data were collected on mice aged 3, 6, and 9 mo. Microcomputed tomography (µCT) was performed on maxillae where 3-dimensional images were generated and bone loss was assessed. Decalcified sections of specimens were scored for inflammation and stained with tartrate-resistant acid phosphate (TRAP) to visualize osteoclasts. Immunophenotyping was performed on single-cell suspensions isolated from primary and peripheral lymphoid tissues using flow cytometry. Results presented indicate that TTP KO mice had significantly more alveolar bone loss over time compared with WT controls. Bone loss was associated with significant increases in inflammatory cell infiltration and an increased percentage of alveolar bone surfaces apposed with TRAP+ cells. Furthermore, it was found that the draining cervical lymph nodes were significantly enlarged in TTP-deficient animals and contained a distinct pathological immune profile compared with WT controls. Finally, the oral microbiome in the TTP KO mice was significantly different with age from WT cohoused mice. The severe bone loss, inflammation, and increased osteoclast activity observed in these mice support the concept that TTP plays a critical role in the maintenance of alveolar bone homeostasis in the presence of oral commensal flora. This study suggests that TTP is required to inhibit excessive inflammatory host responses that contribute to periodontal bone loss, even in the absence of specific periodontal pathogens.

Activation of vitamin D in the gingival epithelium and its role in gingival inflammation and alveolar bone loss

“…These images were rotated with a standard orientation and threshold to discern mineralized and non‐mineralized tissue. The region of interest (ROI) was indicated by the contour height of molars (M1‐M3) at the cementoenamel junction as the width and the molar cusp tips to root apices as the height as recently reported . Depth was equal to the buccolingual size of the teeth plus 1.0 mm 3 .…”

“…The region of interest (ROI) was indicated by the contour height of molars (M1-M3) at the cementoenamel junction as the width and the molar cusp tips to root apices as the height as recently reported. 26 Depth was equal to the buccolingual size of the teeth plus 1.0 mm 3 . Bone volume fraction was calculated as the percentage of bone within the ROI using AnalyzePro software (Seattle, WA).…”

“…26 7μm sections were stained with tartrate-resistant acid phosphate (TRAP) and aniline blue (counterstain) to quantify osteoclast cellular endpoints in the interradicular area as recently reported. 26 TRAP-positive area (red-color staining) and eroded bone perimeters were quantified using Visiopharm software (Hoersholm, Denmark). Data are reported in accordance with standardized nomenclature.…”

Myeloid-Derived Suppressor Cells at the Intersection of Inflammaging and Bone Fragility

“…Besides MDSCs being macrophage progenitors, which can also become osteoclasts, we and others have suggested that MDSCs may directly become osteoclasts in the right bone microenvironment-either in the context of aging or cancer (Sawant and Ponnazhagan 2013;Steinkamp HM 2018). Indeed, we show in Figure 3, that MDSCs or circulating monocytes (CD11b + LY6G − LY6C high ) isolated from 12-week-old mice can differentiate directly into osteoclasts in response to RANKL/M-CSF.…”

“…Likewise, it is not known of the same mechanisms of MDSC differentiation into osteoclasts are operative compared to other osteoclastogenic populations. However, our group has recently shown that mice deficient in the RNA binding protein, tristetraprolin, where there is significant amounts of TNF-α being expressed, have an increased expansion of MDSC population and increased bone loss in the alveolar bone (Steinkamp HM 2018). Ongoing studies are addressing the potential mechanisms.…”