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Role of Nitric Oxide in Orthodontic Tooth Movement (Review)

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Role of Nitric Oxide in Orthodontic Tooth Movement (Review) INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 48: 168, 2021 Role of nitric oxide in orthodontic tooth movement (Review) TONG YAN1,2*, YONGJIAN XIE3*, HONGWEN HE2, WENGUO FAN2 and FANG HUANG1 1Department of Pediatric Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055; 2Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510080; 3Department of Orthodontic Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China Received March 22, 2021; Accepted June 8, 2021 DOI: 10.3892/ijmm.2021.5001 Abstract. Nitric oxide (NO) is an ubiquitous signaling tooth movement. Orthodontic tooth movement is a process molecule that mediates numerous cellular processes associ‑ in which the periodontal tissue and alveolar bone are recon‑ ated with cardiovascular, nervous and immune systems. NO structed due to the effect of orthodontic forces. Accumulating also plays an essential role in bone homeostasis regulation. evidence has indicated that NO and its downstream signaling The present review article summarized the effects of NO on molecule, cyclic guanosine monophosphate (cGMP), mediate bone metabolism during orthodontic tooth movement in order the mechanical signals during orthodontic‑related bone to provide insight into the regulatory role of NO in orthodontic remodeling, and exert complex effects on osteogenesis and osteoclastogenesis. NO has a regulatory effect on the cellular activities and functional states of osteoclasts, osteocytes and periodontal ligament fibroblasts involved in orthodontic tooth Correspondence to: Professor Fang Huang, Department of movement. Variations of NO synthase (NOS) expression Pediatric Dentistry, Hospital of Stomatology, Sun Yat‑sen University, levels and NO production in periodontal tissues or gingival 56 Lingyuan Xi Road, Guangzhou, Guangdong 510055, P.R. China crevicular fluid (GCF) have been found on the tension and E‑mail: [email protected] compression sides during tooth movement in both orthodontic Dr Wenguo Fan, Guangdong Provincial Key Laboratory of animal models and patients. Furthermore, NO precursor and Stomatology, Guanghua School of Stomatology, Sun Yat‑sen NOS inhibitor administration increased and reduced the tooth University, 74 Zhongshan Road 2, Guangzhou, Guangdong 510080, movement in animal models, respectively. Further research P. R. Ch i na is required in order to further elucidate the underlying E‑mail: [email protected] mechanisms and the clinical application prospect of NO in orthodontic tooth movement. *Contributed equally Abbreviations: NO, nitric oxide; cGMP, cyclic guanosine Contents monophosphate; NOS, nitric oxide synthase; L‑arg, L‑arginine; nNOS, neuronal NOS; eNOS, endothelial NOS; iNOS, inducible 1. Introduction NOS; sGC, soluble guanylyl cyclase; PKG, cGMP‑dependent protein kinases; PDE, phosphodiesterase; PDL, periodontal ligament; CGRP, 2. Orthodontic tooth movement overview calcitonin gene‑related peptide; M‑CSF, monocyte/macrophage 3. Effects of NO on orthodontic tooth movement colony‑stimulating factor; RANKL, receptor activator of nuclear 4. Conclusions and future perspectives factor‑κB ligand; OPG, osteoprotegerin; IL, interleukin; TNF, tumor necrosis factor; PGE2, prostaglandin E2; cAMP, cyclic adenosine monophosphate; MMPs, matrix metalloproteinases; Runx2, 1. Introduction transcription factor runt‑related transcription factor 2; BMP, bone morphogenetic protein; TGF, transforming growth factor; MAPK, Nitric oxide (NO) is a water‑soluble, gaseous, short‑lived free mitogen‑activated protein kinase; HIF, hypoxia‑inducible factor; radical molecule that plays multifaceted roles in a broad range VEGF, vascular endothelial growth factor; FSS, fluid shear stress; of physiological and pathological processes in mammals (1‑3). ECM, extracellular matrix; Cx, connexin; FAK, focal adhesion NO is produced by NO synthase (NOS) as a consequence of kinase; ODQ, 1H‑(1,2,4)oxadiazolo‑(4,3‑a)quinoxalin‑1‑one; ERK, extracellular signal‑regulated kinase; PI3K, phosphoinositide the process of L‑arginine (L‑arg) conversion into L‑citrulline 3‑kinase; Akt, protein kinase B; PFF, pulsed fluid flow; GCF, gingival with the participation of oxygen and nicotinamide adenine crevicular fluid; L‑NAME, N(G)‑nitro‑L‑arginine methyl ester dinucleotide phosphate. Three isoforms of NOS have been identified: Neuronal NOS (nNOS) and endothelial NOS Key words: NO, cGMP, orthodontic tooth movement, bone (eNOS) are constitutively expressed calcium‑dependent remodeling, osteoblast, osteoclast enzymes, characterized by the rapid production of a small amount of NO; inducible NOS (iNOS) is a calcium‑independent enzyme that is upregulated at the transcriptional level during 2 YAN et al: NITRIC OXIDE IN ORTHODONTIC TOOTH MOVEMENT inflammation, causing a relatively slow yet increased‑output pressure side, the reduction of blood flow and the distortion NO production (2,3). The most common target of NO is of nerve endings in PDL may cause hypoxia and the release soluble guanylate cyclase (sGC), which generates the second of vasoactive neurotransmitters, including substance P, calci‑ messenger cyclic guanosine monophosphate (cGMP) from tonin gene‑related peptide (CGRP), and vasoactive intestinal guanosine‑5'‑triphosphate within the cell (4,5). cGMP mainly polypeptide. As a result, vasodilatation and the aggregation of acts on protein kinase G (PKG) and can be degraded by phos‑ circulating leukocytes, monocytes, macrophages, lymphocytes phodiesterase (PDE), such as PDE5, 6 and 9 (2,6). The effect and mast cells has been observed (22‑26). Growth factors, of NO on bone mass regulation and bone metabolism has been chemokines and other cytokines also contribute to these well investigated and reviewed elsewhere; however, studies processes (23,27,28). on the involvement of NO in orthodontic tooth movement are Osteoclasts are multinucleated cells, that initially differ‑ limited (7‑9). entiate from multipotential hematopoietic precursors in the Tooth movement induced by orthodontic force is achieved monocyte/macrophage lineage, upon macrophage‑colony through bone remodeling, as a result of the sequential stimulating factor (M‑CSF) and receptor activator of nuclear transduction of molecular signals and changes in cellular factor‑κΒ ligand (RANKL) stimulation, which are secreted behaviors (10,11). It is of utmost significance to determine primarily by cells of the osteoblast lineage (29‑35). M‑CSF the underlying mechanism of orthodontic tooth movement, in promotes the proliferation, adhesion and migration of osteo‑ order to reduce possible side‑effects and shorten the duration clast precursor cells (36‑38). RANKL promotes the fusion, of therapy. NO is extensively involved in orthodontic‑related differentiation and bone resorptive function of osteoclasts biological events, such as aseptic inflammation, mechanical through the activation of RANK on the surface of osteoclast signal transduction and bone remodeling. Furthermore, the precursors (33,39,40). OPG, a decoy receptor for RANKL, regulatory effect of NO on bone remodeling has been demon‑ suppresses osteoclastogenesis through the blockage of the strated to be cGMP‑related (12,13). In the present review, the RANK/RANKL signaling pathway (41,42). regulatory effects of NO on the functional states of related The aseptic inflammatory response caused by orth‑ cells and tissues during orthodontic tooth movement, as well odontic forces is indispensable for tooth movement (11,43). as the possible mechanisms involved are discussed, with the Interleukin (IL)‑1β, IL‑6, tumor necrosis factor (TNF)‑α aim of providing helpful insight towards the application of and prostaglandin E2 (PGE2) can induce the release of effective therapeutic interventions in orthodontics. RANKL and MCS‑F to stimulate osteoclast precursor differentiation (41,44‑47). In addition to the enhancement 2. Orthodontic tooth movement overview of osteoclastogenic factor expression, TNF‑α also activates osteoclast precursors directly through it binding to TNF Orthodontic tooth movement relies upon periodontal ligament receptor (32,48,49). PGE2 enhances the bone‑resorbing (PDL) and alveolar bone remodeling. The PDL is a dense activity of osteoclasts through the increase of intracellular connective tissue that plugs the tooth to the adjacent alveolar cyclic adenosine monophosphate (cAMP) levels or the partial bone (14,15). It contains collagen fiber bundle, blood vessel, mediation of TNF‑α (50). Mature osteoclasts occupy small nerves, interstitial fluids and multiple cell types, including cavities termed Howship's lacunae, in which hydrogen ions fibroblasts, osteoclasts, osteoblasts and macrophages (10,14). and proteolytic enzymes are released, including cathepsin K The alveolar bone consists of bone cells (osteoclasts, osteo‑ and matrix metalloproteinases (MMPs), in order to degrade blasts and osteocytes) and the mineralized matrix (14,16). The the bone matrix (39,51,52). When the magnitude of the force force applied to the tooth triggers cell‑signaling cascades in decreases, osteoclasts become inactive and detach from the the PDL and the alveolar bone, leading to tissue remodeling bone (53). and tooth movement (11,17). Orthodontic tooth movement can be organized into three Tension side: Osteoblasts and bone formation. Bone depo‑ phases: i) The initial phase; ii) lag phase; and iii) post‑lag sition induced by osteoblasts presents is the predominant phase (18). In
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