RANKL deletion in periodontal ligament and bone lining cells blocks orthodontic tooth movement

Abstract

The bone remodeling process in response to orthodontic forces requires the activity of osteoclasts to allow teeth to move in the direction of the force applied. Receptor activator of nuclear factor-κB ligand (RANKL) is essential for this process although its cellular source in response to orthodontic forces has not been determined. Orthodontic tooth movement is considered to be an aseptic inflammatory process that is stimulated by leukocytes including T and B lymphocytes which are presumed to stimulate bone resorption. We determined whether periodontal ligament and bone lining cells were an essential source of RANKL by tamoxifen induced deletion of RANKL in which Cre recombinase was driven by a 3.2 kb reporter element of the Col1α1 gene in experimental mice (Col1α1.CreERTM+.RANKLf/f) and compared results with littermate controls (Col1α1.CreERTM−.RANKLf/f). By examination of Col1α1.CreERTM+.ROSA26 reporter mice we showed tissue specificity of tamoxifen induced Cre recombinase predominantly in the periodontal ligament and bone lining cells. Surprisingly we found that most of the orthodontic tooth movement and formation of osteoclasts was blocked in the experimental mice, which also had a reduced periodontal ligament space. Thus, we demonstrate for the first time that RANKL produced by periodontal ligament and bone lining cells provide the major driving force for tooth movement and osteoclastogenesis in response to orthodontic forces.

Core Matrisome Protein Signature During Periodontal Ligament Maturation From Pre-occlusal Eruption to Occlusal Function

“…Given its control also of fibroblast differentiation, it is possible that asporin controls the interaction between PDL fibroblasts, osteoblasts and osteoclasts in the formation of Sharpey's fibers. These observations are also supported by previous studies showing that induction of the RANKL/OPG system in PDL fibroblasts leads to osteaoclast genesis and bone resorption in the event of tooth movement and compressive forces in the PDL (Yang et al, 2018). This is a mechano-sensitive process (Jacobs et al, 2013).…”

Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review

“…65 RANKL is a member of the membrane-associated TNF ligand superfamily and is detected on osteoblasts, bone marrow stromal cells, activated T cells, periodontal ligament fibroblasts, cementoblasts and endothelial cells. [66][67][68][69] RANKL binds its receptor, receptor activator of NF-κB (RANK), expressed on the osteoclast precursor cells, resulting in the activation of the osteoclast. 70 The binding of RANKL to RANK finally activates the transcription of NFATc1, c-Fos and NF-κBrelated genes, which are upregulated in periodontitis 71,72 and modulate the proliferation, differentiation and activation of osteoclasts.…”

Local injection of RANKL facilitates tooth movement and alveolar bone remodelling

“…Shiotani et al (Shiotani, Shibasaki, & Sasaki, 2001) have shown the presence of RANKL in periodontal tissues during experimental tooth movement. RANKL produced by periodontal ligament and bone lining cells provide the major driving force for tooth movement and osteoclastogenesis in response to orthodontic forces (Yang et al, 2018). Local RANKL injection can recruit peripheral monocytes and macrophages (Jin, Li, & Yu, 2011) and has the ability to produce inflammatory cytokines such as interleukin (IL)-1b, IL-6, IL-11 and tumour necrosis factor-alpha (TNFα), which probably mediate bone remodelling by stimulating RANKL expression during orthodontic tooth movement (Kohli & Kohli, 2011;Saito, Saito, Ngan, Shanfeld, & Davidovitch, 1991).…”