## 1 Introduction  
The World Health Organization (WHO) considers malocclusion one of the most important oral health problems. Malocclusion has repercussions on the quality of life associated with oral health. It ranks as the third most widespread dental issue in oral health; first is caries and second is periodontitis [1]. Malocclusion is a developmental condition marked by irregular associations between the alignment of teeth and the structure of dental arches [2]. Severe malocclusion can lead to both physiological and psychological effects, including impairments in chewing function, speech articulation, and aesthetic appearance. This can have a lasting negative impact on self-esteem and social interactions over time [3]. The origin of malocclusion is complex and influenced by a combination of genetic and environmental factors. Among these, the skeletal pattern, determined by genetic factors, is considered the primary contributor to the development of malocclusion [4]. However, the importance of certain environmental factors has been emphasized, including atypical swallowing, mouth breathing, and deleterious oral habits (such as thumb sucking, nail biting, or prolonged use of a baby bottle), which can disrupt the natural balance and development of the dental matrix, leading to malocclusion [4; 5]. The treatment for malocclusion is orthodontics, which seeks to achieve aesthetic and functional improvement through mechanical therapy that moves the teeth to a more ideal position [5]. The displacement of teeth during orthodontic treatment is triggered by mechanical stimuli and is facilitated by changes in the periodontal ligament (PDL) and alveolar bone. Periodantal tissues surrounding the tooth root, such as the PDL, alveolar bone, and gums, undergo impact due to orthodontic force resulting from mechanical stress. The periodontal ligament (PDL) is a versatile fibrous tissue responsible for connecting the cement covering the tooth root to the alveolar bone, functioning as the primary, and a highly sensitive, receptor. The PDL detects mechanical stimuli induced by the application of orthodontic force [6; 7; 8; 9]. In a more detailed context, when force is exerted on a tooth, osteoclast activity is triggered on the pressure side. Simultaneously, the multiplication and differentiation of periodontal ligament (PDL) fibroblasts and mesenchymal stem cells (MSCs) lead to increased bone production by osteoblasts on the tension side. Furthermore, mechanical force promptly initiates various cell signaling pathways in osteoblasts, including calcium (Ca2+), nitric oxide (NO), interleukin-1 (IL-1), and adenosine triphosphate (ATP). The process of orthodontic tooth movement (OTM) results in the release of mediators such as NO and IL. Fluid shear stress can activate the Ca2+ signaling system, stimulating ATP release, prostaglandin E2 (PGE2) secretion, and osteoblast development. On the compression side, localized hypoxia and a decrease in blood flow in the PDL occur simultaneously. Hypoxia-inducible factor 1 (HIF-1), a transcription factor, activates the expression of Vascular Endothelial Growth Factor (VEGF) and receptor activator of nuclear factor-kappa ligand (RANK-L) in PDL fibroblasts and osteoblasts, triggering osteoclast differentiation and inducing bone resorption in the compression areas. The relationship between bone resorption and formation becomes evident during the remodeling of the alveolar bone surrounding the tooth's root during orthodontic movement [10; 11]. The receptor activator of nuclear factor-kappa B (RANK), RANK ligand (RANK-L), and osteoprotegerin (OPG) systems play a pivotal role in orchestrating bone remodeling. This intricate process entails the involvement of the tumor necrosis factor (TNF)-related ligand RANK-L and its two receptors, RANK and OPG [12; 13]. More specifically, RANK-L controls the development and activation of osteoclasts. When RANK-L binds to the RANK receptor on osteoclast lineage cells, osteoclast precursors express RANK, a receptor for RANK ligand (RANK-L).