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Host modulation therapy

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Host modulation therapy

  1. 1. Host modulation therapy Dr. Vijay Apparaju PG Student (2013-14 batch) 1
  2. 2. C O N T E N T S Definitions Introduction History Rationale Targets of host modulation therapy Modulation of arachidonic acid metabolites NSAIDS COX1 and COX2 inhibitors Selective COX2 inhibitors Lipoxins Triclosan Omega 3 fatty acids Modulation of Bone remodeling Bisphosphonates osteoprotegerin estrogen, selective estrogen receptor Modulation of Matrix metalloproteinases Exogenous Tetracyclines SDD Chemically modified Tetracyclines 2
  3. 3. C O N T E N T S 3 endogenous TIMP αmacroglobulins Modulation of Cytokines Modulation of other host inflammatory mediators Nitrous oxide nuclear factor kappa B Periodontal vaccines local host modulating agents Combination therapy Disruption of cell signaling pathways NFkB pathway MAPK pathway disruption of RANK/RANKL/osteoprotegerin axis conclusion
  4. 4. Definitions: Host : “The organism from which a parasite obtains its nourishment.” Modulation: “The alteration of function or status of something in response to a stimulus or an altered chemical or physical environment” (Taber's Medical Dictionary, 2004) 4
  5. 5. Host modulation therapy: Treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or down regulating destructive aspects of host response and up regulating protective or regenerative responses.(CARRANZA10th ed) 5
  6. 6. 6
  7. 7. 7
  8. 8.  The concept of host modulation was first introduced to dentistry by Williams (1990) and Golub et al (1992).  In 1990, Williams concluded, "There are compelling data from studies in animals and human trials ; that pharmacologic agents that modulate the host responses believed to be involved in the pathogenesis of periodontal destruction may be efficacious in slowing the progression of periodontitis."  In 1992, Golub host modulation with tetracyclines and their chemically modified analogues.  Initially, adjunctive therapies were solely antimicrobial, such as the use of antiseptics and antibiotics. New adjunctive approaches involve modulation of the host response. History 8
  9. 9. • To aid host in its fight against infectious agents by supplementing the natural inherent defensive mechanisms • To modify host response by changing the course of inflammatory system  Arachidonic acid metabolites  Matrix metalloproteinases  Cytokines  Other inflammatory mediators  Nitric oxide  Nuclear factor kappa β  Endothelial cell adhesion molecules  Reactive oxygen species  Bone metabolism 9
  10. 10.  When considering factors that increase an individual's risk for developing periodontitis, it has been recognized that genetic, environmental (e.g., tobacco use), and acquired risk factors (e.g., systemic disease) can increase a patient's susceptibility to developing this disease.  These risk factors may lead to the imbalance between the proinflammatory and anti-inflammatory mediators seen in susceptible individuals  HMTs are systemically or locally delivered pharmaceuticals that are prescribed as part of periodontal therapy and are used as adjuncts to conventional periodontal treatments, such as scaling and root planing (SRP) and surgery. 10
  11. 11. • Use of systemic HMTs for treatment of a patient's periodontal condition may also provide benefits for other inflammatory disorders, such as arthritis, cardio- vascular disease, dermatologic conditions, diabetes, and osteoporosis  HMTs do not "switch off" normal defense mechanisms or inflammation; instead, they ameliorate excessive or pathologically elevated inflammatory processes to enhance opportunities for wound healing and periodontal stability.  And also they can affect onset, rate of progression, and severity of periodontal disease, as well as response to therapy. Some of these risk factors can be modified to reduce a patient's susceptibility 11
  12. 12. 12 Courtesy : clinical periodontology,Carranza 10 th ed
  13. 13. Modulating arachidonic acid metabolites • NSAIDS • Lipoxins • Triclosan • Omega-3 fatty acid 13
  14. 14. 14 Courtesy :Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47
  15. 15. 15 Courtesy : clinical periodontology,Carranza 10 th ed
  16. 16. Non-steroidal antiinflammatory drugs (NSAIDS) 16
  17. 17. • Various NSAIDs have been studied in regulating periodontal disease. • They are Non selective COX inhibitors IBUPROFEN KETOPROFEN (3% or enantiomer capsules 10mg) FLURBIPROFEN COX-2 INHIBITORS PREFERENTIAL COX-2 INHIBITORS MELOXICAM SELECTIVE COX-2 INHIBITORS CELECOXIB ROFECOXIB • First HMT with NSAID was with Indomethacin in ligature induced canine periodontitis rat model. 17
  18. 18. Disadvantages as a HMT for periodontitis. • Administration for extended periods is necessary for periodontal benefits to become apparent, and are associated with significant side effects: – Gastrointestinal problems, – Hemorrhage (from decreased platelet aggregation), – Renal and hepatic impairment. – Rebound effect 18
  19. 19. – use of selective COX-2 inhibitors reduce periodontal inflammation without the side effects typically observed after long-term (nonselective) NSAID therapy. – selective COX-2 inhibitors slowed alveolar bone loss in animal models(Bezerra MM jp 1993) and modified prostaglandin production in human periodontal tissues (Vardar S JPeriodontol 2003). However, the selective COX-2 inhibitors were later identified to be associated with significant and life-threatening adverse effects, resulting in some drugs being withdrawn from the market. 19
  20. 20. Role of arachidonic acid metabolites. Mode of interception Significant Contributors Agents employed Author’s coments Prostaglandins and other arachidonic acid metabolites within the periodontal tissues play a role in the pathogenesis. Inhibition of arachidonic acid metabolite by blocking of the cyclooxygenase pathway Goldhaber et al (1973) Nyman et al (1979) Weaks- Dybvig et al (1982) Offenbacher et al (1987) Jeffcoat et al (1991) Indomethacin, Flurbiprofen, S-Ketoprofen, Triclosan. Systemic daily administration for periods up to three years ,showed significant reduction in rate of bone loss, major disadvantage of rebound effect 20
  21. 21. Author Purpose Host M Agent Parameters Subjects Results Ishihara y, nishihara t et al (1991) demonstrate the lipopolysaccharide isolated from a.a comitans strain induced bone resorption Indomethacin dexamethasone PGE2 and IL- 1 levels Mouse PGE2 and IL-1 participate in LPS induced bone resorption in vitro. Howell th, fiorellini i, weber hp et al (1991) To study the effects of piroxicam in preventing gingival inflammation and plaque formation Piroxicam Gingival inflammation plaque index Beagle dogs Significantly inhibit the development of gingival inflammation Roy S, Feldman, Szeto B et al (1983) To evaluate the effect on bone resorption: A retrospective study Aspirin (asp) or aspirin plus indomethcin Radiographs Humans Percentage bone loss for the entire dentition was lower in asa group Offenbacher S, Odle BM et al (1989) metabolites of cyclooxygenase (co) during the progression of periodontitis Flurbiprofen Crevicular fluid levels of PGE2 and TXB2 Rhesus monkey prevented rise in TXB2, but did not affect increase in PGE2. Heasman PA, et al (1993) efficacy of flurbiprofen (50mg) on both developing and established gingivitis Flurbiprofen GCF concentration of PGE2, TXB2 and LTB4, Bleeding index Human control gingival inflammation with both preventive and therapeutic Properties shown after 9 months 21
  22. 22. • A series of oxygenated arachidonic acid derivatives • They have a number of immunomodulatory and anti-inflammatory actions 22
  23. 23. • Lipoxins are short lived endogenously produced substances • At present two lipoxins have been identified; lipoxin A4 (LXA4) and lipoxin B4 (LXB4). • Recently observed from peripheral blood neutrophils in patients with aggressive periodontitis • Also found in GCF • Disrupts the chemotaxis of PMN. • Administration of metabolically stable analogues of lipoxins blocked P.Gingivalis induced neutrophil infiltration and also reduced PGE2 levels • Suggests that these may involve in regulation of acute local inflammatory response Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47 23
  24. 24. • Well known and widely used lipid soluble anti bacterial agent • Have anti-bacterial and anti-inflammatory agent • Inhibits cyclooxygenase and lipooxygenase pathways • Reduced TNFα levels • Use of dentifrice containing sodium fluoride (0.243%),triclosan (0.3%) with 2.0% PVM/MA copolymer (poly vinyl methyl maleic acid) reduced the PD and CAL. Gaffar, A.,Scherl, D:The effect of triclosan on mediators of gingival inflammation.,J Clin Periodontol 1995,22,480-484 24
  25. 25. • Inhibition of cyclooxygenase and lipooxygenase pathway (arachidonic acid cascade • Reduction of prostanoids and leukotriens especially leukotriene B4 Vardar S, Buduneli E, Baylas H, Berdeli AH, Buduneli N, Individual and combined effects of selective cyclooxygenase-2 inhibitor and omega- 3 fatty acid on endotoxin-induced periodontitis in rats. J Periodontol 2005:76: 99– 106 25 • Omega-3 fatty acid regulates inflammatory cytokine/mediator messenger RNA expression in Porphyromonas gingivalis- induced experimental periodontal disease
  26. 26. • Bisphosphonates • Osteoprotegerin • Estrogen and selective estrogen receptor modulators(HRT) 26
  27. 27. • The bisphosphonates are bone-seeking agents . inhibit bone resorption by disrupting osteoclast activity. • Two types non nitrogenous and nitrogenous • Interfere with osteoclastic metabolism and secretion of lysosomal enzymes (Weinreb M et al J Periodontal 1994) possess anticollagenase properties (Nakaya H et al J Periodontol 2000) • Treatment with the bisphosphonate significantly increased bone density compared with placebo ( Reddy MS et al J Periodontol 1995) • In human studies also, these agents resulted in enhanced alveolar bone status and density (Rocha M et al J Periodontol 2001) • The ability of bisphosphonates to modulate osteoclast activity may be useful in the treatment of periodontitis, Bisphosphonates 27
  28. 28. • Some bisphosphonates have the unwanted effects – inducing changes in white blood cell counts. – avascular necrosis of the jaws following bisphosphonate therapy, with the resultant risk of bone necrosis following dental extractions (Carter G, Goss AN Med J Aust 2005) • Bisphosphonate-related osteonecrosis of the jaw, although primarily associated with intravenous administration of bisphosphonates rather than oral administration, • Has impeded the development of bisphosphonates as an HMT to manage periodontitis. • As with NSAIDs, at present there are no bisphosphonate drugs that are approved and indicated for treatment of periodontal diseases 28
  29. 29. 29
  30. 30. Tissue level Cellular level molecular level • ↓osteoclast recruitment • ↑increased osteoclast apoptosis • ↓osteoclast adhesion • ↓depth of resorption rate • ↓release of cytokines by macrophages • Inhibit mevalonate pathway – increase in apoptosis • Post translational phenylation of GTP binding proteins • ↓bone resorption • ↓bone turnover • ↑Number of new bone multicellular units • New positive whole body bone balance 30
  31. 31. Author Purpose Host modulating agent Parameters Subjects Results Shoji K,Horiuchi H (1995) Efficacy of risendronate to prevent alveolar bone resorption Risendronate Bone mineral density Rats. In preventing bone resorption in periodontitis M young H , P ark JY et al (2 001 ) evaluate the clinic al availability of bisphosphonate in auto genous free bone grafts Bisphosphonates Clinical measurements, histomorphologic al review Rats Clinical application of bisphosphonates for decreasing resorption of grafted bone Durate P M , Gurgel B C D e t a l (2 0 0 5 To evaluate whether alendronate (ald) influence Bone healing around titan ium implants Alendronate Estrogen levels rats . Alendronate may prevent negative influence of estrogen deficiency on bone healing around titanium implants Howell 1991, His- Ming 2004, Holzhausen 2005, Gurkan 2005, Durate 2005. Inhibition of osteoclast/MM P activity through chelation of cations. Bisphosphonates (Alendronate), Hormone replacement therapy.(HRT), OPG- Fc therapeutic agents Osteoporosis and osteopenia may be indicators for periodontal diseases. humans improves the clinical outcome of nonsurgical periodontal therapy and may be an appropriate adjunctive treatment to preserve periodontal bone mass. 31
  32. 32. • Inhibits bone loss, bone turnover • Increases bone density • As inhibits osteoclastic activity and differentiation by regulating production of stimulatory cytokines. Promotes osteoclasts apoptosis 32 Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47
  33. 33. 33
  34. 34. 34 • Matrix metalloproteinases(MMPs) are considered to be primary proteinases involved in periodontal tissue destruction by degradation of extracellular matrix molecules
  35. 35. • Polymorphonuclear leukocyte type collagenase (MMP-8) and gelatinase (MMP-9) as the source of excess active enzymes present (Golub et al, 1997) • MMP-13 (collagenase-3) is believed to be a mediator of bone resorption and cartilage destruction and has been identified in GCF from chronic periodontitis patients. (Golub et al, 2001) • 35 • Found in neutrophils, macrophages, fibroblasts, epithelial cells, osteoblasts and osteoclasts
  36. 36. MMP inhibitors Exogenous Zn,Ca chelating agents Phosphorus containing peptides Sulfur based inhibitors Endogenous TIMPS α2 macroglobulins Biology of the Periodontal Connective Tissues, P. Mark Bartold, A. Sampath Narayanan Tetracyclines CMTs SDDs
  37. 37. • Several synthetic MMP inhibitors are being studied in clinical trails • Some Zinc and calcium chelating agents (EDTA and phenanthroline) are potent inhibitors of enzyme activity invitro but are toxic and not used invivo. • Multiple synthetic peptides have been formulated in an attempt to synthesize more specific chelators including phosphorus-containing peptides, sulfur-based inhibitors and peptidyl hydroxamic acid derivatives, these also found as toxic in vivo • The synthetic MMP inhibitors most extensively investigated are the family of tetracycline antibiotics, which can inhibit host-derived MMPs by mechanisms independent of their antimicrobial properties. 37
  38. 38. Anti microbial activity Zn++, Ca++ chelating Host modulating activity 38
  39. 39. • Sub-antimicrobial-dose doxycycline (SDD) is a 20- mg dose of doxycycline that is approved and indicated as an adjunct to SRP in the treatment of chronic periodontitis. • It is taken twice daily for 3 months, up to a maximum of 9 months of continuous dosing. 39 Sub antimicrobial dose of doxycyclines as an adjunct to scaling and root planing : post treatment effects, J Clin Periodontol 2001; 28: 782–789
  40. 40. • Studies have found no detectable antimicrobial effect on the oral flora or the bacterial flora in other regions of the body. • At present SDD is the only systemically administered HMT specifically indicated for the treatment of chronic periodontitis that is approved by the US Food and Drug Administration (FDA) and accepted by the American Dental Association (ADA). 40
  41. 41. Courtesy: Philip M preshew,Host response modulation in periodontitis Periodontology 2000,vol 48, 2008,92-110 41
  42. 42. • Golub et al (J Periodont Res 1985). reported that the semisynthetic compound (e.g., doxycycline) was more effective than the parent compound tetracycline in reducing excessive collagenase activity in the GCF of chronic periodontitis patients. • Because of its safety profile, pharmacokinetic properties, and ready systemic absorption. to eliminate the side effects of long-term tetracycline therapy, especially the emergence of tetracycline-resistant organisms, SDD capsules were prepared and tested( Golub LM1985) 42
  43. 43. • Each capsule contained 20 mg of doxycycline versus the commercially available 50 mg and 100 mg, antimicrobially effective, capsules or tablets. • clinical studies using sub-antimicrobial doses of doxycycline have shown no difference in the composition or resistance level of the oral flora (Thomas J; jp 2000) • No overgrowth of opportunistic pathogens, such as Candida, in the oral cavity, gastrointestinal system, or genitourinary system. 43
  44. 44.  Golub et al 1985 reported that a 2-week regimen of SDD reduced collagenase in GCF and in the adjacent gingival tissues surgically excised for therapeutic purposes.  He found using SDD therapy adjunctive to routine scaling and prophylaxis cause continued reductions in the excessive levels of collagenase in the GCF after 1 month of treatment. 44
  45. 45. 45 After cessation of SDD administration, however, there was a rapid rebound of collagenase activity , suggesting that a 1-month treatment regimen with this host modulation agent was insufficient to produce a long-term benefit(Ashley RA 1999) In contrast, during the same study, a 3-month regimen produced a prolonged drug effect without a rebound in collagenase levels to baseline during the no-treatment phase of the study. these reductions in collagenase levels were gains in the relative attachment levels in the SDD group( Ashley RA 1999)
  46. 46. allergy or hypersensitivity to tetracyclines.  pregnant or lactating women or children less than 12 years old (because of the potential for discoloration of the developing dentition). reduce the efficacy of oral contraceptive. There is a risk of increased sensitivity to sunlight (manifested by an exaggerated sunburn) seen with higher doses of doxycycline, although this has not been reported in using the sub-antimicrobial dose. 46
  47. 47. 47  During the late 1980s, it was discovered that tetracyclines have an inhibitory effect on MMP activity  This led to the development of chemically modified tetracyclines (CMTs), which have lost their antimicrobial activity but retain their anti-MMP activity.  Development of resistant bacteria and gastrointestinal toxicity seen with parent tetracyclines is not produced by CMTs  CMT 1–10 has proposed till now  CMT-3 and -8 appear to be the most potent inhibitors of MMP activity. CMT-1 also affects MMP activity, but it is less powerful  A marked decrease of MMP-2 mRNA levels is found in keratinocytes by CMT-1 and CMT-3 Chemically modified tetracyclines stimulate matrix metalloproteinase-2 production by periodontal ligament cells, J Periodont Res 2006; 41; 463–470
  48. 48. TIMPS (Tissue inhibitors of MMPS)  Forms classic non-covalent bio-molecular complexes with MMPs.  inhibit the activity of the fully competent MMP.  Block or retard the MMP precursor activation.  So balance should be there  Though TIMP levels increases in pathological conditions this increase may not compensate for elevated concentrations of MMPs  Recombinant TIMPs can reduce bone resorption Hill P, Raynolds, Inhibition of stimulated bone resorption in vitro by TIMP 1, TIMP2. Biochem biophys Acta 1993, 1171-1174 48 α2 macroglobulin • Regulates MMPS in body fluids
  49. 49. 49
  50. 50. 1. IL-1 Receptor antagonist 2. TNF-α Receptor antagonist • Catabolic activities of cytokines are regulated by endogenous inhibitors like × The progression of inflammatory cells towards alveolar crest × The recruitment of osteoclasts × Periodontal attachment and bone loss • IL4, IL10,IL11, TGFβ are natural counteract for pro inflammatory cytokines • Recombinant IL11 reduced disease progression in ligature induced periodontitis canine model (Martscelli et al2000) 50
  51. 51. Recombinant human iL4, IL 10, Granulocyte colony stimulating factor Macrophages,lymphocytes etc IL1 TNFα Reactive oxygen intermediates NO 51
  52. 52. • Nitric oxide • Administration of NO inhibitor (mercaptoethylguanide) - decreased bone loss in rat model (Lohinal et al 1998) 52 • inducible NOS (iNOS) is responsible for nitric oxide (NO) production by epithelial and inflammatory cells in response to proinflammatory cytokines in some inflammatory diseases (Lappin et al. 2000) • Although NO has an antimicrobial protective activity, its elevated concentration in the tissues has a cytotoxic effect toward the host cells.
  53. 53. 53 Periodontal vaccines local host modulating agents Combination therapy Disruption of cell signaling pathways NFkB pathway MAPK pathway disruption of RANK/RANKL/osteoprotegerin axis JAK-STAT pathway conclusion
  54. 54. 54 The development of vaccines is an important strategy against serious infectious diseases that do not have effective treatments recent findings of associations between periodontitis and other systemic diseases may provide a rationale for the development of a vaccine against periodontitis Vaccination is the most effective medical intervention against viral pathogens As the association of Epstein–Barr virus and periodontitis was suggested (Slots J, Contreras, Oral Microbiol Immunol2000:15: 277–280.) Phosphoryl choline is a common bacterial antigen, and a substantial proportion of the bacteria in dental plaque (30–40%) bear phosphoryl choline antigen(Schenkein HA et al, Infect Immun1999:67: 4814–4818) Antibody to phosphoryl choline is produced by B-1 cells, and is increased in periodontitis patients. B-2 cells reside in lymphnodes and also produce high affinity antibodies.
  55. 55. 55 • In a non-human primate model, formalin killed P. gingivalis whole-cell vaccine induced serum antibody • The induced antibody inhibited prostaglandin E2 production by mononuclear cells stimulated with lipopolysaccharide. (Roberts FA, Houston LS, Lukehart SA, Mancl LA, Persson GR, Page RC. Periodontitis vaccine decreases local prostaglandin E2 levels in a primate model. Infect Immun 2004:72: 1166–1168) • Among the P. gingivalis antigens, fimbriae and enzymes such as arginine-specific gingipains and lysine-specific gingipain have been investigated as possible candidates for vaccine antigens. • Immunization with P. gingivalis fimbriae also protected against periodontal destruction in rats(Evans RT, Infect Immun 1992:60: 2926–2935.)
  56. 56. 56Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47
  57. 57. 57 Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47
  58. 58. 58
  59. 59. ¶ Enamel matrix proteins ¶ Bone morphogenetic proteins (BMP-2, BMP-7), ¶ Growth factors (platelet-derived growth factor) ¶ Insulin like growth factor. ¶ Tetracyclines. 59 Philip M preshew,Host response modulation in periodontitis Periodontology 2000,vol 48, 2008,92- 110
  60. 60. • The locally applied HMTs currently approved by the FDA for adjunctive use during surgery are – Enamel matrix proteins (Emdogain), – Recombinant human platelet-derived growth factor-BB (GEM 21S), – BMP-2 (INFUSE).  All topically administered NSAIDs have not been approved as local HMTs for the management of periodontitis. Eg : ketoprofen racemic cream 1%,enantiomer dentifrice 0.3%, 60 Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47
  61. 61. • The initial local host modulatory agent approved by the FDA for adjunctive use during surgery to assist with clinical attachment gain and wound healing was Emdogain; • EMD may affect gingival health by ways other than cell proliferation/survival, i.e. by stimulation of TIMP-3 production,which could improve the MMP–TIMP balance in gingival tissue and extracellular matrix destruction when applied locally. (Zeldich, E et al Journal of Periodontal Research. Apr2010, Vol. 45 Issue 2, p200-206) • platelet-derived growth factor combined with a resorbable synthetic bone matrix (GEM 21S) to assist in regenerative procedures , wound healing, particularly in patients with diabetes • rhBMP-2 (INFUSE) soaked on to an absorbable collagen sponge to assist with ridge and sinus augmentation and healing of fractures by the orthopedic community. 61
  62. 62. • SDD (20mg, bid) + flurbiprofen (50mg,4 times a day) • CMT + Flubiprofen (Leung MK, J Rheumatol 1995: 22:1726–1731.) • CMT8 + Bisphosphonate (clodronate) (Llavaneras A, Ramamurthy NS., J Periodontol 2001: 72:1069–1077.) • SDD + locally delivered doxycycline gel (10% attridox) (Novak MJ, J Periodontol2008:79: 33–41.) 62 (Lee HM, Ciancio SG, J Periodontol 2004:75: 453–463).
  63. 63. • NO synthase inhibitors:- • Nitric oxide synthase (NOS) inhibitors have protective effects against bone resorption and inflammatory process in periodontitis in rats. • Lappin et al. in 2000 reported that inducible NOS (iNOS) is responsible for nitric oxide (NO) production by epithelial and inflammatory cells in response to proinflammatory cytokines in some inflammatory diseases such as rheumatoid arthritis and periodontal disease. 63
  64. 64.  Although NO has an antimicrobial protective activity, its elevated concentration in the tissues has a cytotoxic effect toward the host cells.  Leitao et al. in 2005 found a reduction of alveolar bone loss and gingival inflammation after the use of a selective iNOS inhibitor – mercaptoethylguanidine – confirming that NO has a deleterious role in the pathophysiology of periodontitis and that its modulation may prevent tissue destruction. 64
  65. 65. 65
  66. 66. 66
  67. 67. • Bacterial components activate many signal transduction pathways . – Mitogen-activated protein kinase (MAPK) pathway, – Phosphatidylinositol-3 protein kinase (PI3) pathway, – Janus kinase-signal transducer and activator of transcription (Jak-STAT), – Nuclear factor kappa B (NF-kB) . 67
  68. 68. TRAF NFkB + IkB iKB Kinase NFkB Proteasome inhibitors • Inhibition of IkB degradation • Over expression of IkB • Inhibition of protein kinases that activates IkB 68
  69. 69. 69
  70. 70. • MPKs divided into 3 families • Extracellular signal regulated kinases (ERK1/2) • JNKs • P38 • Mitogen, growth factors activates ----- ERK1/2 • Proinflammatory cytokines, • Cell stress inducing factors • JNKs • P38 • 3 families of activation of many transcriptional factors -- Activator protein1, NFkB • mostly P38 activates - NFkB 70
  71. 71. MAPK 71
  72. 72. 72
  73. 73. 73
  74. 74. • RANKL : OPG is increased in periodontitis patients in GCF • Other cells like CD4-Tcells also express RANKL during inflammation • Osteoprotegerin can be used as therapeutic agent (simonet et al) • Eg: murine osteoprotegerin- Fc Protein • Gene therapy for the lifelong delivery of osteoprotegerin has also been proposed • Osteoprotegerin expressing adenovirus vectors provided sustained and efficacious levels of circulating osteoprotegerin • AMGN-0007 a genetically engineered osteoprotegerin- Fc construct was shown to be effective in inhibiting bone resorption (Teng et al 2001) 74
  75. 75. References References: 1.Clinical periodontology , Carranza 10 th editiom 2. Host response modulation in periodontics., Periodontology 2000, Vol. 48, 2008, 92–110 3. Host responses in periodontal diseases: a preview, Periodontology 2000, Vol. 43, 2007, 9–13 4. Toll gates to periodontal host modulation and vaccine therapy, Periodontology 2000, Vol. 51, 2009, 181–207 5. Host-Response Therapeutics for Periodontal Diseases, J Periodontol 2008;79:1592- 1600. 6.Modulation of host response in periodontal therapy ,J Periodontal 2002,73,,460- 470. 7. Modulation of Host PGE2 Secretion as a Determinant of Periodontal Disease Expression., J Periodontol 1993;64:432-444 8. Host-Response Therapeutics for Periodontal Diseases, J Periodontol 2008;79:1592- 1600. 9. Chemically modified tetracyclines stimulate matrix metalloproteinase-2 production by periodontal ligament cells., J Periodont Res 2006; 41; 463–470 10. A Decade of Bisphosphonate Bone Complications: What It Has Taught Us About Bone Physiology, The International Journal of Oral & Maxillofacial Implants 75
  76. 76. 11. Bisphosphonates in Periodontal Treatment: A Review ., Oral Health Prev Dent 2009; 7: 3–12 12.Periodontal host modulation with anti-proteinase, anti-inflammatory andbone sparing agents, a systematic review.,Ann Periodontal,vol8, number 1, December 2003. 76
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