Cytokines and Orthodontic tooth movement

Transcription

1 Review Cytokines and Orthodontic tooth * Dr. Sharath Kumar Shetty, **Dr. Mahesh Kumar. Y, *** Dr. Smitha. P. L. * HOD and Professor, Director-PG Studies, ** Professor, *** PG Student Dept. of Orthodontics and Dentofacial Orthopaedics, KVG Dental College & Hospital, Sullia. D.K.. Abstract The main aim of this study is to evaluate cytokines in the gingival crevicular fluid (GCF) during orthodontic treatment, summarizing the regulation patterns of the most commonly studied cytokines and their clinical implications. Association exists between Prostaglandin E 2 (PGE 2 ) and Interleukin-(1L-1β) and pain, velocity of the tooth and treatment mechanics. IL-1β and PGE 2 showed different patterns of upregulation with IL-1β being more responsive to mechanical stress and PGE 2 more responsive to synergistic regulation of IL-1β and mechanical force. The results might be taken to support, at the cellular level, the use of light continuous forces for orthodontic treatment. Key words: Gingival crevicular fluid, Cytokines, Orthodontic tooth, Interleukin-1β. Journal of Dental Sciences & Research 2:1: Pages Introduction During orthodontic treatment, the early response of periodontal tissues to mechanical stress involves several metabolic changes that allow tooth. The PDL, the soft tissue matrix that joins the dental root to the alveolar bone, is composed of an intricate network of blood vessels, and nerve endings, the principal cellular components. Orthodontic force produces a distortion of PDL matrix resulting in an alteration in cellular shape and cytoskeletal configuration, neuropepitide release, from afferent nerve endings. At the bimolecular level, these forces may induce the release of PGs, growth factors and cytokines. 1 Successful orthodontic tooth requires the remodeling of the periodontium, the particularly alveolar bone. When a small force is applied for a prolonged period, an inflammatory event occurs, with 132 Journal of Dental Sciences and Research

2 in the periodontium, resulting in bone resorption that accommodates the of the tooth. 2 Mechanical stress from orthodontic appliances is considered to induce cells in the periodontium to form biologically active substances, such as cytokines and enzymes, responsible for connective tissue remodeling. These substances can be monitored non-invasively in humans by following changes in the compositions of GCF during orthodontic tooth. 3 The interest of most reports was focused on the presence of new mediators and on the upregulation, down-regulation of the levels of these regulatory proteins in different treatment designs. 4 Among the more than 100 regulatory proteins detected in GCF, this review will focus on cytokines. Cytokines are biologically active substances expressed by the cells in the periodontium in response to mechanical stress. IL-1 is a polypeptide cytokines produced primarily by cells of the mononuclear phagocytic lineage. Target cell type includes osteoblasts and IL-1 generally promotes proinflammatory response. 5 The pleiotropic action of cytokines include numerous effects on cells of immune system and modulation of inflammatory response. Many characteristic features of cytokines makes them particularly interesting to orthodontics, as cytokines in GCF reflect the local microenvironment of periodontal tissue, the area where upon the effect of orthodontic force is exerted. Materials and Methods A number of key databases (medline, pubmed, embase, web of science) were searched in Jan 2010, using mesh terms of orthodontics tooth and crevicular fluid and using the free text terms of GCF, cytokines, inflammatory factors, regulatory proteins, tooth displacement, canine distalization, and root resorption. The search results from each databases were combined. The inclusion criteria were: human studies on GCF, cytokines (including prostaglandins, tumor necrosing factor, Interleukins, growth factors, colony-stimulating factors, and interferons) or their receptors as study mediators, orthodontic mechanics, GCF sampling and handling methods, cytokines measured, number of study subjects >= 5, or number of study teeth >= 10, proper oral hygiene control, no use of antibiotic/anti-inflammatory drugs before tooth and GCF sampling. The exclusion criteria were: animal studies, in vitro studies, studies on human GCF enzymes or any metabolic products other than mentioned in the inclusi on criteria. 133 Journal of Dental Sciences and Research

3 The data were extracted in 3 categories 1.Orthodontic mechanics Number of study subjects, age of study subjects, control systems and tooth and treatment mechanics (appliances, force magnitudes, force reactivations) studied. 2. GCF sampling and handling methods Most studies had a sampling time of 30s and sampled repeatedly with either no time interval or with intervals of 1min, 5 min, 10 min. The storage temperature was o c, or o c. The cytokine levels were presented differently and expressed in terms of weight, of total GCF protein or of total GCF volume. So, the sampling methods (paper strips, volume/weight measuring, repeated sampling), storage systems (buffer, temperature) and cytokine measurements (assays, total amount/, measurement units) were studied. 3. Cytokine measurements Duration of the study, number of samples, time-points and sites (pressure/tension), target cytokines, up-regulation or down-regulation and peak levels were studied. Cytokines levels were up-regulated in most studies and many cytokines peak at 24h, irrespective of treatment mechanics. RESULTS The studies are listed in Table1 (orthodontic mechanics), Table2 (GCF sampling methods) and Table3 (cytokine measurements). 134 Journal of Dental Sciences and Research

4 Table 1 : GCF cytokines and orthodontic tooth : Orthodontic mechanics Reference N Age Control Tooth Force System Force Reactivations (yr) (cn) Baseline UCI,LI Fixed orthodontic treatment - No Base Line UIM,CI Modified hyrax appliance - Yes,1week ±1 Baseline UC Hybrid Retractor, - No Distraction ±4 Antagonistic UC Sectional, 60,120, No Distalizing 240N Antagonistic UM Separation Elastics - No Baseline UC NiTi, aligning - No ±3 Control & UC Elastic Chain, 250 No antagonistic distalyzing ±2 Control & UC Elastic Chain, 250 No antagonistic distalyzing ±2 Baseline UC NiTi, - No aligning Antagonistic UM Separation Elastics - No ±2 Contralatera UC Elastic Chain, 250 No l distalyzing ±2 Control & Antagonistic UC Elastic Chain, distalyzing 250 No Antagonistic UC Sectional, 18,60 No distalyzing Baseline LC,UC Sectional, distalyzing 90,115 No Antagonistic UC, LC Sectional, distalizing 100 Yes, 1 Week Contralatera ULI NiTi 70 No l aligning Contralatera ULI NiTi 70 No l aligning Antagonistic UC Sectional, distalizing 18,60 No Control & UC Elastic chain 250 No Antagonistic distalizing Control& Antagonistic UC Elastic chain distalizing 250 No Baseline UC Elastic ligature, 150 No distalizing Contralatera l ULI NiTi, Aligning 100 No Tooth -UM, upper molar: LC, lower canine: UC, upper canine: UCI, upper central incisor: ULI, upper lateral incisor. 135 Journal of Dental Sciences and Research

5 Table-2 GCF sampling and handling methods Reference Sampling duration (sec) Repeated sampling Storage temperature ( 0 C) Measuring total amount/ Expressing in min -80 Total protein ng /µl Protein pg /1min -80 Concentration pgµl /1min -70 Protein ng µl No -70 Total amount pg No -20 Concentration pg µl /min -30 Concentration pg µl min -30 Concentration pg µl No -20 Total amount pg No -70 Total amount pg /0min -30 Protein /1min -30 Protein /1min -70 Protein /1min -70 Total amount /1min -70 Protein /5 min -80 Total amount /1 min -70 Protein /1 min -30 Protein /1 min -30 Protein pg µg -1 ng µl -1 ng µl -1 pg pg µl -1 Pg µg -1 pg pg µl -1 IL-1β in ngg -1 pg/ µg -1 pg µg No - Total amount ng /1 min -80 Total amount pg 136 Journal of Dental Sciences and Research

6 Table 3 Cytokine measurements Ref Duration Sampling Cytokine U/D Peak Main results points 6 7d - OPN RANKL - - Increased levels of OPG, RANKL with root resorption during Orthodontic tooth 7 21d 3,8,30days IL-1β & BG - 24 hr Increased levels of IL - 1β & BG during orthodontic /orthopedic force application 8 7d 0,1,24,168 hours 9 84d 0,1,3,7,14,28, 42, 56,70,84d 10 14d 0,1min,1h,1d, 7d IL-1β PGE months 0,7,21,6month IL-1β s +7d,21d TNF-α 12 7d 0,1,24,168 h RANKL OPG 13 7d 0,1,24,168 h RANKL OPG 14 6 months 0,7d,21d,6mon IL-2 ths +7d,+21d IL-6 IL d 0,1,24,168 h Ih-1β Pg E 2 TNF-α 24 hr Hybrid no change with time distraction higher than hybrid IL-1β - - Tooth rate relate to IL-1ra IL-1 gene polymorphisms 24 hr Higher levels in tension sites. Higher levels in tension sites - - Tend to increase Tend to increase UP 24 hr Lower ratio values in adults Down Lower ratio values in adults UP 24 hr No changes at 1hr/168h Down No changes at 1hr/168h - - Tend to increase 7d,back at 21d - - Decrease at 7d, back to baseline Down 7 d at 21d Associated with pain at 24h Weak association with pain at 1hr 16 7d 0,1,4,8,24,72,1 IL-1β Correlated with P substance 20,168,h 3 7d 0,1,24,168hr t-pa Increased only at 24h PAI 5 84d -28,- 24,0,1,3,14,28, IL-1β IL-1ra - - The ratio of the 2 correlate with the rate of tooth 42,56,70,84d 17 30d 0,1,24,6,10,30 d IL Tend to increase with early phase 18 3week 0,1,24,168h Repeat twice IL-1β 24h Higher level at reactivate PGE 2 24h Remain higher for 1week 19 0, PGE 2 regulated in both age groups IL-6 GM-CSF - Increased only in youngsters Increased only in adults 20 84d -28,- 14,0,1,3,14,28, 42,56,70,84d IL-1β IL-1.G 21 7d 0,1,24,1684 IL-1β IL-6 EGF TNF-α <3day <3day No changes No changes at 1 hr or 168 hr No changes at 1hr or 168hr No changes at 1hr or 168hr No changes at 1hr or 168hr 22 7d 0,1,24,1684 TGF-B1 No change at 1 hr / 168 hr 1 5 min 0,5 min TNF-α - More than twofold increase 137 Journal of Dental Sciences and Research

7 2 7d 0,1,24,48,168h r IL-1β PGE 2 24h Increased at 1h, back to baseline at 168hr Stay high at 48h, back to baseline at 168hr. TNF-α, Tumor necrosis factor :IL-Iβ, interleukin 1β : IL-Ira, Interleukin I receptor antagonist: PGE 2,Prostaglandin :RANKL, Receptor activator of nuclear factor-kb ligand: OPG,Osteoprotegerin: IL-2, Interleukin 2: IL-6, Interleukin 6: IL-8, Interleukin 8: t-pa, tissue-type plasminogen activator : TGF-B1, Transforming growth factor: EGF, Epidermal growth factor :PAI,Plasminogen activator inhibitor :GM-CSF, Granulocyte macrophage colony-stimulating factor, U/D, up-regulation or down-regulation. Discussion This is an attempt to review systematically evaluated studies on Cytokines that are expressed in GCF during orthodontic tooth. Most of the results were the peak levels of the various Cytokines measured 24h after applying an orthodontic force, irrespective of treatment mechanics. GIANNOPOULOU et.al 15 reported that the intensity of pain at 1h was associated with PGE 2 levels, where as pain intensity at 24h was associated with IL-1β levels. VAMAGUCHI et al 16 showed a significant correlation between IL-1β and substances P, a peptide involved in pain, neurotransmission, during orthodontic treatment in adults. IWASAKI et al 5, 20 found a positive correlation with the IL- 1β:IL-1 receptor antagonist(il- 1ra) ratio. They suggested that the speed of tooth is related to stress and to IL-1 gene cluster polymorphisms. Interlukin-6 and granulocyte macrophages colony stimulating factor (GM- CSF)showed less responsiveness in adults than in Juveniles. 12,19 LEE et.al 18 compared the production of pge 2 and IL-1β to continuous/interrupted force, showed different responses: PGE 2 levels showed less consistent changes with different force regimens than IL-1β. IL-1β levels may reach a significant elevation between 1h. 10,15,2 SUGIYAMA et al 23 found that amount of Cathepsin B ingcf is increased by orthodontic tooth. This increased Cathepsin B may be involved in extracellular matrix degradation in response to mechanical stress. The peak of IL-1βhas been observed at 24h, 16,18,21 and 72h. 1 Without force reactivation, IL-1β has been shown to decrease significantly at 168h to baseline level, but with force reactivation it reached an even higher peak. 21 A heavy decaying force1 6,21 tend to result in a significant 138 Journal of Dental Sciences and Research

8 decrease of the IL-1β at 168h.Light continuous force 5,18,20 tend to maintain relatively high IL-1β levels for a larger period and thus may reduce the frequency of reactivations. INGMAN 24 demonstrated that in vivo in human GCF, elevation and partial activation of multiple species of Polymorphonuclear and Fibroblast type Matrix metalloproteinase-8 reflect periodontal remodeling during orthodontic tooth. EMEL SARI and CIHAN UCAR 25 demonstrated that microscrew implants did not show increased 1L-1β levels during orthodontic tooth. This supports the concept that microscrew implants might be useful as absolute anchorage devices. REN et al 26 found that once the microenvironment of periodontal tissue is activated by an orthodontic force, several key Proinflammatory cytokines are produced to trigger a cascade of cellular events. References 1. Lowney J.J, Norton L.A, Shafer D.M, Rossomando E.F :Orthodontic forces increase tumor necrosis factor alpha in the human gingival sulcus.am J Orthod 1995;108: Grieve W.G, Johnson G.K, Moore R.N, Reinhardt R.A, Dubois L.M :Prostaglandin E and interleukin-1 B levels in the gingival crevicular fluid during human orthodontic tooth.am J Orthod 1994;105: Hoshino-Itoh J, Kurokawa A, Yamaguchi M, Kasai K: levels of t-pa and PAI-2 in gingival crevicular fluid during orthodontic tooth in adults.aus Orthod 2005;21: Ren Y, Vissink A: Cytokines in crevicular fluid and orthodontic tooth : Eur J Oral Sci 2008;116: Iwasaki L.R et al.tooth and cytokines in gingival crevicular fluid and whole blood in growing and adult subjects: Am J Orthod 2005;128: PASCHOS et al 27 observed parameters as well as 1L-1βlevels reflected the higher impact of bands on gingival health. These values showed a significant decrease after application of a chlorhexidine containing varnish, the Plaque index showed higher values for the teeth with brackets. 139 Journal of Dental Sciences and Research 6. Evans C.A, Georgel A: Detection of root resorption using dentine and bone markers :Orthod Craniofac Res 2009;3: Tzannetou S, Efstratiadis S, Nicolay O, Grbic J, Lamster I: Comparison of levels of inflammatory mediators 1L-1B and BG in gingival crevicular fluid from molars, premolars, and

9 incisors during rapid palatal expansion.am J Orthod 2008;133: from periodontal ligament cells in vitro:orthod Craniofacial Res2006;9: Karacay S, Saygun I, Bengi A.O, Serdar M: Tumor necrosis factor alpha levels during two different canine distalization techniques.angle Orthodontist ;77: Iwasaki L,R, Gibson C.S, Crouch L.D, Marx D.B, Pandey J.P, Nickel J.C: speed of tooth is related to stress and 1L-1 gene polymorphisms.am J Orthod 2006;130: Dudic A, Killiaridis S, Mombelli A, Giannopoulou C: composition changes in gingival crevicular fluid during orthodontic tooth :comparisons between tension and compression sides. Eur J Oral Sci 2006;114: Basaran G, Ozer T, Kaya F.A, Kaplan A,Hamamci O: Interleukin -1 B and tumor necrosis factor alpha levels in the human gingival sulcus during orthodontic treatment.angle orthod 2006;76: Kawasaki K, Takahashi T, Yamaguchi M, Kasai K. Effects of aging on RANKL and OPG levels in gingival crevicular fluid during orthodontic tooth. Orthod Craniofacial Res2006;9: Nishijima Y et al. levels of RANKL and OPG in gingival crevicular fluid during orthodontic tooth and effect of compression force on releases 140 Journal of Dental Sciences and Research 14. Ozer B.G, Kaya F.A, Hamamci O: Interleukins 2,6 and 8 levels in human gingival sulcus during orthodontic treatment.am J Orthod 2006;130: Giannopoulou C, Dudic A, Kiliaridis S: Pain discomfort and crevicular fluid changes induced by orthodontic elastic separators in children.the Journal Pain 2006;5: Yamaguchi M, Yoshii M, Kasai K: Relationship between substance P and interleukin-1b in gingival crevicular fluid during orthodontic tooth in adults. Eur J Orthod 2006;28: Tuncer B.B et al.levels of interleukin -8 during tooth.angle orthod 2005;75: Lee et al.effects of continuous and interrupted orthodontic force on interleukin - 1B and Prostaglandin E2 production in gingival crevicular fluid.am J Orthod 2004;125: Ren Y et al. Cytokine levels in crevicular fluid are less responsive to orthodontic force in adults than in juveniles.j Cli Periodontol 2002;29: Iwasaki L.R, Haack J.E, Nickel J.C, Reinhardt R.A, Petro T.M:Human interleukin-1b and Interleukin -1 receptor antagonist secretion and velocity of tooth

10 . Archives of Oral Biology 2001;46: Uematsu S, Mogi M, Deguchi T: Interleukin-1B,1L-6, Tumor necrosis factor-alpha, Epidermal growth factor, and B2 Microglobulin levels are elevated in gingival crevicular fluid during human orthodontic tooth. J Dent Res 1996;75: Uematsu S,Mogi M, Deguchi T.Increase of transforming growth factor-b1 in gingival crevicular fluid during human orthodontic tooth.archs Oral Biol 1996;41: Sugiyama Y et al.the level Cathepsin B in gingival crevicular fluid during human orthodontic tooth.eur J Orthod 2003;25: Ingman T, Apajalahti S, Mantyla P, Savolainen P, Sorsa T: Matrix metalloproteinase-1 and 8 in gingival crevicular fluid during orthodontic tooth :Eur J Orthod 2005;27: Sari E, Ucar C: Interleukin - 1 B levels around microscrew implants during orthodontic tooth. Angle Orthod 2007;77: Ren Y, Hazemeijer H, Haan B, Qu N, Vos p: Cytokine profiles in crevicular fluid during orthodontic tooth of short and long durations. J Periodontol2007;78: Paschos E et al.orthodontic attachments and chlorhexidine containing varnish effects on gingival health.angle Orthod 2008;78: Journal of Dental Sciences and Research