RANKL+ senescent cells under mechanical stress: a therapeutic target for orthodontic root resorption using senolytics

Abstract

In dentistry, orthodontic root resorption is a long-lasting issue with no effective treatment strategy, and its mechanisms, especially those related to senescent cells, remain largely unknown. Here, we used an orthodontic intrusion tooth movement model with an L-loop in rats to demonstrate that mechanical stress-induced senescent cells aggravate apical root resorption, which was prevented by administering senolytics (a dasatinib and quercetin cocktail). Our results indicated that cementoblasts and periodontal ligament cells underwent cellular senescence (p21+ or p16+) and strongly expressed receptor activator of nuclear factor-kappa B (RANKL) from day three, subsequently inducing tartrate-resistant acid phosphatase (TRAP)-positive odontoclasts and provoking apical root resorption. More p21+ senescent cells expressed RANKL than p16+ senescent cells. We observed only minor changes in the number of RANKL+ non-senescent cells, whereas RANKL+ senescent cells markedly increased from day seven. Intriguingly, we also found cathepsin K+p21+p16+ cells in the root resorption fossa, suggesting senescent odontoclasts. Oral administration of dasatinib and quercetin markedly reduced these senescent cells and TRAP+ cells, eventually alleviating root resorption. Altogether, these results unveil those aberrant stimuli in orthodontic intrusive tooth movement induced RANKL+ early senescent cells, which have a pivotal role in odontoclastogenesis and subsequent root resorption. These findings offer a new therapeutic target to prevent root resorption during orthodontic tooth movement.

The neutrophil–osteogenic cell axis promotes bone destruction in periodontitis

“… 33 , 58 , 60 The intronic enhancer in osteocytic cells is activated by cellular senescence signals, 58 which were also shown to stimulate RANKL expression in periodontal ligament cells and cementoblasts. 61 We previously demonstrated that periodontitis-induced bone loss and osteoclast development were markedly suppressed when RANKL was deleted in osteoblastic cells and periodontal ligament cells. 4 In our scRNA-seq dataset, the osteoblastic cells (characterized by expression of Sp7 and Runx2 ) and periodontal ligament fibroblasts (characterized by expression S100a4 and Postn ) were clustered as a single population due to the limited number of cells compared to previous scRNA-seq studies.…”

Connecting epigenetics and inflammation in vascular senescence: state of the art, biomarkers and senotherapeutics

“…They observed that cultured human diploid fibroblasts exhibited a finite number of divisions (40–60 population doublings), a phenomenon attributed to intrinsic factors, which were later identified as telomere shortening. Different external and internal stress and developmental signals trigger cellular senescence in response to cellular damage, including telomere shortening, DNA damage, oncogenic activation, radiation, oxidative and genotoxic stress, epigenetic changes, perturbed proteostasis, mitochondrial dysfunction, inflammation, nutrient deprivation and mechanical stress ( Kuilman et al, 2010 ; Muñoz-Espín et al, 2013 ; Storer et al, 2013 ; Hernandez-Segura et al, 2018 ; Kumari and Jat, 2021 ; Huang et al, 2022 ; Zhou et al, 2023 ).…”