host modulation, pathogenesis, perioceutics, periodontics, host modulatory agents, HMT, MMPs, Cytokines

1. 1

2. HOST MODULATION THERAPY -
II
PRESENTED BY:- DR K. ABHILASHA
MODERATED BY:- DR FOUZIA TARANNUM
DEPARTMENT OF PERIODONTICS
M. R. AMBEDKAR DENTAL COLLEGE
2

3. OVERVIEW FROM PART 1
 INTRODUCTION
 HISTORICAL PERSPECTIVE
 MODELS OF PERIODONTAL PATHOGENESIS
 HOST RESPONSE AND PERIODONTAL DISEASE
 HOST MODULATION THERAPY
 Definition
 History
 RATIONALE
 CLASSIFICATION
 MODULATION OF ARACHIDONIC ACID METABOLITE
3

4. CONTENT- PART 2
 MODULATION OF MATRIX METALLOPROTEINASES
 MODULATION OF CYTOKINE
 MODULATION OF BONE REMODELLING
 MODULATION OF OTHER HOST INFLAMMATORY MEDIATORS
 LOCAL HOST MODULATING AGENTS
 FUTURE DIRECTIONS
 CONCLUDING COMMENTS
 REFERENCES
4

5. MODULATION OF MATRIX
METALLOPROTEINASE
5

6. 1. WHAT ARE MMPs???
Structurally Related But
Genetically
Distinct Enzymes
1962, Gross & Lapiere
(Tadpole Collagenase)
1966, Fullmer
(Human Gingival Collagenase)
Also known as
MATRIXINS
Belongs to METZINCIN
superfamily
6

7. Secretion and Activation
Secreted by lymphocytes and
granulocytes, but in particular by
ACTIVATED MACROPHAGES
ZYMOGENS
Activated By
PROTEOLYTIC
CLEAVAGE
7

8. Secretion and Activation
 MMPs are not constitutively expressed in most tissues but are induced temporarily in
response to exogenous signals such as various cytokines, growth factors, cell matrix
interactions, and altered cell-cell contacts.
 These increase significantly in various pathologic conditions that may lead to unwanted
tissue destruction such as
Inflammatory diseases,
Tumor growth,
Diabetes and
Metastasis
8

9. TYPES OF MMPs
 Based on substrate specificity and molecular structure
 Based on structural consideration
Sl.no. Enzyme Number
1. Interstitial collagenase MMP-1
2. Neutrophil collagenase MMP-8
3. Collagenase 3 MMP-13
4. Gelatinase A MMP-2
5. Gelatinase B MMP-9
6. Stromeolysin -1 MMP-3
7. Stromeolysin- 2 MMP-10
8. MT-1 MMP MMP-14
9. MT-2 MMP MMP-15
10. MT-3 MMP MMP-16
11. MT-4 MMP MMP-17
12. Matrilysin-1 MMP-7
13. Matrilysin-2 MMP-26
14. Metaloelastase MMP-12
15. Enamelysin MMP-20
9

10. ROLE IN PERIODONTAL DESTRUCTION
 It has been found that MMP-8 activity of human cell origin in gingival tissues and
gingival crevicular fluid in periodontitis patients and in peri-implant sulcular fluid of
periimplantitis patients is higher than in healthy subjects.
 MMP-8 released from neutrophils in a latent, inactive pro-form becomes activated by
the independent and/ or combined actions of host- and microbial-derived proteases
and ROS produced by triggered neutrophils, thus leading to destruction.
10

11. ROLE IN BONE DESTRUCTION
A number of studies have suggested that osteoblasts express
Fibroblast collagenase(FIB-CL) when stimulated by bone-
resorbing agents
Result in dissolution of the un-mineralised collagenous
osteoid layer
Osteoblasts later vacate the surface as newly-recruited
osteoclasts move in
Destruction of bone (expression of MMP is an early event in
bone resorption)
11

12. Destructive MMPs in periodontitis (Golub et al. 1995, 1998)
Enzyme Primary cellular
source
Description
MMP-8 PMN Collagenase.
A dominant MMP in GCF during
Periodontitis
MMP-9 PMN Gelatinase.
Also dominant in GCF
MMP-13 Bone, epithelium Collagenase.
Dominant in diseased tissue.
12

13. MMP inhibitor
Endogenous
Tissue inhibitor of
MMP
α2 Macroglobulin Plasma inhibitor of
MMP
Exogenous
13

14.  TIMPs are small (21-28 kDa), multi-functional proteins that regulate MMP function both at
the level of their activation and in their ability to hydrolyze a particular substrate.
 TIMPs appear to regulate matrix degradation both by proteinase elimination and by
blockage of autolytic MMP activation.
 Active MMPs are captured by α-macroglobulin by a unique venus-fly-trap mechanism
activated by cleavage of a bond in the “bait region”.
 The rapid capture rates, play an important role in regulation of MMP activity.
14

15. Exogenous MMPIs:
 Phosphorous containing peptides
 Sulfur based inhibitors of MMPs
 Hydroxamic acid derivatives:
The broad-spectrum hydroxymate MMPIs, Batimastat (BB- 94) and Marimastat (BB-
2516) were the first MMPIs to enter clinical trials in the treatment of malignant tumors
 The nonpeptidomimetic MMPIs include tetracyclines and bisphosphonates.
15

16. TETRACYCLINES
16

17. TETRACYCLINE
 The major anti-proteinase used in periodontal treatment is tetracycline (TC).
 In addition to its antimicrobial activity, this group of compounds has the capability of
inhibiting the activities of
 Neutrophils,
 Osteoclasts, and
 MMP (specifically MMP-8)
thereby working as an anti-inflammatory agent that inhibits bone destruction.
17

18. Inhibition Of Collagen Breakdown By TCs
 Collagenase production by host cells and excessive activity in diseased tissues has been
considered a key, rate limiting step in pathologic collagen destruction including that
associated with periodontal disease.
 The property of tetracycline family to down regulate MMP activity was first identified in
the early 1980’s, by Ramamurthy & Golub
 Thus it was recognized that the inhibition of tissue collagenolysis by tetracyclines
represented a new therapeutic modality in the management of periodontal disease, and
intense research began to identify the most effective dosing regimens.
18

19. Golub et al reviewed some of the characteristics of the anti-proteolytic activity of TCs
including:
 Their specificity against collagenases from different cellular sources (e.g., collagenase
from inflammatory cells is quite sensitive to TC, while that from fibroblasts is relatively
resistant.
 The site on the TC molecule responsible for anticollagenase activity.
19

20.  Golub et al., in 1987 recognized that the antimicrobial and anti collagenase properties of
tetracyclines resided in different parts of the four ringed structure.
 The dimethylamino group from carbon-4 position (the side-chain required for
antimicrobial activity in TCs) of the A ring of the four ringed structure is removed.
 Golub et al in 1998 modified the drug which led to the development of the CMT
20

21. CHEMICALLY
MODIFIED
TETRACYCINE
21

22. ACTIONS OF CMTs
22

23. Potential for periodontal therapy:
 Since the initial demonstration in 1987 of CMT’s ability to inhibit pathologically
excessive collagenase activity in gingiva, a series of studies have supported its
development as a host modulator in periodontal therapy
 Effects on bone resorption (as well as bone formation) are most encouraging.
23

24. Rifkin et al reported that CMT, at levels approximating those found in vivo, can inhibit
parathyroid hormone- induced bone resorption, assessed by Ca release and
histomorphometry, and can produce these beneficial effects with no evidence of cellular
toxicity and at levels lower than those required for minocycline.
Golub et al found that only CMT -1 and CMT – 3 ( not CMT -2 and CMT -4) were able to
block osteoblast collagenase activity, and thus, were able to block bone resorption in
organ culture.
24

25. SUB-ANTIMICROBIAL
DOSAGE OF
DOXYCYCLINE
25

26.  A new approach to non-antibacterial periodontal therapy is the administration of
specially prepared low-dose capsules containing as low as 20 mg of doxycycline.
 Doxycycline is the most potent collagenase inhibitor of commercially available TCs.
 To date, this is ONE approved, systemic therapy that is prescribed as a host response
modifier in the treatment of periodontal disease, and that is adjunctive SDD (Periostat@,
CollaGenex Pharmaceuticals Inc., Newtown, P A, USA), which downregulates the activity
of MMPs.
26

27. 27

28. SDD As An Adjunctive Therapy
 Golub LM in 1994 conducted an experiment with this new formulation and
demonstrated clearly that SDD (20 mg twice daily) administered for just 2 weeks
inhibited collagenase activity by 60-80% in the gingival tissues of patients with chronic
periodontitis
 Their studies indicated that this dosing regimen could prevent periodontitis progression
without the emergence of doxycycline-resistant microorganisms or other typical
antibiotic side-effects
 Thus, the concept was born that SDD (20 mg twice daily) could be used as an adjunct
for treatment of chronic periodontitis
28

29. Sequencing Prescription With Periodontal Treatment
 Not used as monotherapy, Used as an adjunct to SRP
. To be prescribed to coincide with
the first episode of SRP
.
 Taken as 20mg twice daily for 3 months and up to a maximum of 9 months of
continuous dosing.
 After initial periodontal treatment, the patient is enrolled into an intensive maintanence
program. (re evaluation of probing depths, reinforcement of oral hygiene, SRP
,
remotivation of the patient).
29

30. 30
INDICATIONS
 Chronic and aggressive Periodontitis patients treated non surgically. (Caton J et
al, 2000,Preshaw et al 2005)
 Patients traditionally considered resistant to periodontal treatment (smokers).
 Cases considered refractory to treatment and those with risk factors like diabetes and
smoking

31. CONTRAINDICATIONS
 History of allergy or hypersensitivity
 Pregnant and lactating women or children less than 12 yrs of age
 Conditions like gingivitis and periodontal abscess or when an antibiotic regimen is
necessary
 May reduce the effectiveness of oral contraceptives
31

32. MODULATION OF CYTOKINES
32

33. Cytokines
 Stanley Cohen in 1974 -coined the term “cytokines”
 Cytokines can be defined as regulatory proteins controlling the survival, growth, differentiation
and functions of cells.
 Host cytokines are a group of inflammatory mediators highly implicated in periodontal disease
pathogenesis.
33

34.  The inflammatory disease process is characterized by domination of proinflammatory cytokine
mediators.
 External neutralization of inappropriate inflammatory cytokines is a therapeutic strategy can be
attempted in many chronic inflammatory conditions.
 Hence anticytokine therapy was developed.
34

35. Anti cytokine
therapy
Receptor
antagonist
Soluble receptors
Neutralising
antibodies
35

36. Receptors for cytokines
IL- I
IL-1 R I
IL- 1R II
IL-6
TNF-α I
TNF-α II
TNF-α
IL-6 R
Periodontal therapy for periodontal disease is aimed at inhibiting the binding of
cytokines to these receptors present on target cells like fibroblasts, thus no
activation of target cells. For example IL-1ra 36

37. Soluble Cytokine Receptor
 Soluble cytokine receptors are derived from proteolytic cleavage of the extracellular
domain of cell bound cytokine receptors.
 They can be found in blood and extracellular fluid.
 IL -1β sIL-1R
 TNF –α sTNF-R1
sTNF- RII
37

38. Neutralising Antibody
 Anti-cytokine antibodies are also antagonist in function and they
also lower down the levels of cytokine.
 TNF – α Anti- TNF Ab
 IL - 6 Anti – IL-6 Ab
38

39. ANTI-CYTOKINE THERAPY & PERIODONTITIS
 Anti-cytokine agents have shown to significantly reduce
 loss of clinical attachment
 loss of alveolar bone &
 slowing down the progression of experimental periodontal
disease in animal studies
Assuma et al 1998, Graves et al 1998 Delima et al., 2001,
Oates et al 2002, Zhang et al 2004 39

40. RECOMBINANT IL – 11- agent still under research
 Anti inflammatory cytokine
 Inhibits TNF-α & other pro-inflammatory cytokines
 It minimizes tissue injury through stimulation TIMP-1
Martuscelli et al 2000 - subcutaneous injection rhIL-11in experimental periodontitis in
dogs showed significant reduction in the rate of clinical attachment and radiographic bone
loss after an 8-week period.
40

41. MODULATION OF BONE
REMODELLING
41

42.  The cytokines orchestrate the cascade of destructive events that occur in the
periodontal tissues.
 Factors regulating osteoblast and osteoclast activity have become important targets for
developing pharmacological and clinical strategies to modulate the rate of bone
formation and resorption
 Modulation of bone regulation can be done with the use of
 Anti-inflammatory agents
 Chemically modified tetracycline
 Bisphosphonates
42

43. BISPHOSPHONATES
 The bisphosphonates have been known to chemists since the middle of the 19th
century, when the first synthesis occurred in 1865 in Germany.
 Etidronate, the first bisphosphonate to be used,to treat a human disease.
 It binds to the hydroxyapatite crystals of bone and prevents their dissolution by
interfering with osteoclasts function
 Known as bone sparing agents
43

44. Classes of bisphosphonate :
Non-Nitrogen-containing
bisphosphonates:
Etidronate
Clodronate
Tiludronate
Nitrogen-containing
bisphosphonates:
Pamidronte Alendronate Ibandronate
Risedronate Zoledronate Neridronate
Olpradonate
44

45. MECHANISM OF ACTION
 BPN are considered to be powerful “inhibitors of bone resorption”.
OSTEOCLAST OSTEOBLAST
DIRECT EFFECT INDIRECT EFFECT
45

46. Activities of Bisphosphonates on Osteoclast Function
Tissue Level Cellular Level Molecular Level
↓ bone turnover due to
↓ bone resorption
↓ number of new bone
multicellular units
Net positive whole
body bone balance
↓ osteoclast recruitment
↑ osteoclast apoptosis
↓ osteoclast adhesion
↓ depth of resorption site
↓ release of cytokines by
macrophages
↑ osteoblast differentiation
and number
Inhibit mevalonate pathway
(can result in perturbated
cell activity and induction
of apoptosis)
↓ post-translational prenylation of
GTP-binding proteins
Tenenbaum HC et al 2002
46

47. USES OF BISPHOSPHONATES
I. NON MALIGNANT BONE DISORDERS :
A. Osteporosis
B. Paget’s disease
C. Osteogenesis imperfect
D. Fibrous dysplasia
E. Primary hyperthyroidism
II . MALIGNANT DISORDERS
A. Hypercalcemia of malignancy
B. Multiple myeloma of breast cancer that has spread to the bone
III . BISPHOSPHONATES ARE USED AS BONE SCANNING AGENTS 47

48. Nakaya et al. 2000 Findings from in vitro experiments demonstrated that bisphosphonates down-
regulated activity of several MMPs 3, 8 and 13 from human PDL cells
Jeffcoat 1996,
El-Shinnawi2003,
Lane 2005,
Rocha 2001 & 2005
Five human studies that assessed the effect of bisphosphonates as an
adjunctive agent to scaling and root planing in periodontal treatment have
been found to date. They used Alendronate & Risedronate (0.05mg/kg) and
results showed probing depth reduction, clinical attachment gain,
probing reduction, alveolar bone gain and increase in bone mineral
Sharma A, Pradeep AR
2012
The study aimed to explore the clinical efficacy of 1% alendronate (ALN) gel as
a local drug delivery system in adjunct to scaling and root planing for the
treatment of aggressive periodontitis and chronic periodontitis patients
compared to placebo gel. Results showed that delivery of 1% ALN stimulates a
significant increase in PD reduction, CAL gain, and improved bone fill
48

49. SIDE EFFECTS OF BISPHOSPHONATES
 Stomach upset
 Inflammation and erosion of oesophagus
 Fever and flu like symptoms after first infusion which disappears with
subsequent infusions
 Increased risk of electrolyte disturbances
 Marx Roggerio ( 2003) reported that nitrogen containing
bisphosphonates like pamidronate ,zoledronic acid were associated with
“osteonecrosis” of the jaws BRONJ
49

50. MODULATION OF OTHER HOST
INFLAMMATORY MEDIATORS
50

51.  Using the novel strategy
 Disruption of RANKL/OPG axis
 Inhibitors of NF-κB
 Inhibitors MAPK pathways
51

52. 52
RANKL-RANK-OPG SIGNALING PATHWAY
• RANKL
• Receptor activator of nuclear factor kappa B ligand
• Expressed by Osteoblasts
• Plays an important role in osteoclast formation, function and survival
• RANK
• Receptor activator of nuclear factor kappa-B
• Located on osteoclast precursors and mature osteoclast
• OPG
• Osteoprotegrin
• Binds to and inhibits RANKL
• Expressed by osteoblasts and other tissues like spleen, bone marrow, etc
• Protective against bone loss
Osteoblast
RANKL
OPG
Osteoclast
RANK

53. 53
RANKL
RANK RANK
DIFFERENTIATION ACTIVATION
OPG

54. 54

55.  In periodontal disease, the role of RANKL in alveolar bone resorption was first
investigated by Teng et al. 2000.
 Over-expression of RANKL & increased ratio of RANKL/OPG found in patients with
periodontitis Liu et al 2003.
55

56.  The use of OPG as a therapeutic agent was first evaluated by Simon et al. 1997.
 OPG blocked increased osteoclast formation in resorptive processes in periodontal
disease in mice. (Mahamed 2005 & Teng 2006)
 Inhibition of RANKL function with OPG treatment significantly reduced the number of
osteoclasts and the alveolar bone destruction in both studies.
56

57.  Gene therapy for the lifelong delivery of OPG has been proposed for chronic inflammatory
diseases.
 OPG-expressing adenoviral vectors provided its sustained levels that enhanced bone
mineral density and reduced osteoclast numbers for an extended period of time (18
months)
Bolon 2001
The OPG/RANKL/RANK axis is an emerging new target for the
treatment of destructive periodontal disease.
57

58. The NF-κB pathway
 The transcription factors, NF-κB are homo- or heterodimers found in the cytoplasm of
most human cells.
 In vitro studies have established that both P. gingivalis and other periopathogenic
bacteria can activate NF-κB in periodontal tissues.
 NF-κB activation is regulated primarily through IκB and IκB kinase (IKK).
58

59. NF-κB Inhibitors
 Proteasome inhibitors block NF-κB activation by preventing the degradation of IκB and
release of NF-κB.
 Bortezomib (Velcade®) was tested in multiple myeloma with highly promising results
(Richardson P 2003).
 BMS-345541 - decreased both synovial inflammation and joint destruction in an
arthritis model (McIntyre et al 2003).
59

60.  Agents that prevent degradation of NF-kB inhibitors have been investigated to inhibit the nf-
Kb pathway. However, these strategies are still under investigation to be used clinically
60

61. MAPK(Microtubule associated protein kinase) pathway
 Are divided into 3 families: MAPK pathway
Extracellular
signal-regulated
kinases (ERK1/2);
JNKs p38
61

62. All three MAPK families are assumed to be expressed in diseased
periodontal tissues, although the level of expression may differ depending
upon the exact cell types activated and the degree of inflammation
In addition, p38 MAPK controls the synthesis of other compounds,
including chemokines, metalloproteinases and prostaglandins.
62

63.  Studies have shown that inhibition of these signalling pathways can lead to the reduction
in the synthesis of proinflammatory cytokines.
 However, more human trials are required to prove their efficacy as host modulating
agents in periodontal diseases.
63
MAPK Inhibitors

64. LOCAL HOST MODULATING AGENTS
64

65. LOCALLY ADMINISTERED AGENTS
 These are the host modulation agents that are used locally to improve the wound healing and to
stimulate periodontal attachment apparatus.
 Example- Enamel matrix proteins (Emdogain), BMPs, (BMP-2, BMP-7), Growth Factors (PDGF,
Insulin Like Growth Factor,) etc
 ADVANTAGES:-
 Easy and targeted application
 High drug concentration, locally
 Reduced systemic side effects e.g. G.I. disturbance
65

66. EMDOGAIN
 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.
 Promote PDL fibroblast proliferation and growth
 Stimulates release of autocrine growth factors by PDL undifferentiated mesenchymal
cells.
 Stimulates osteoprotegrin, thus triggering osteoblasts and indirectly inhibiting
osteoclasts
66

67.  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
67

68. FUTURE PERSPECTIVES
68

69. 69
 Glucocorticoid-induced ANNEXIN-A1- Annexin A1 level in circulating neutrophils are under the
control of glucocorticoids that involves Annexin A1 Lipoxin A receptor (ALXR). It resolves
inflammation by inhibiting transmigration and recruitment of PMNs cells at the inflammatory site.
The efficacy of Annexin A1 as a host modulation agent in the treatment of periodontitis needs to be
investigated, especially on humans before its clinical application
 Polyenolic zinc binding compounds (PEZBINS)- These compounds have been developed to inhibit
MMPs and cytokines in periodontal and other collagen destructive and inflammatory diseases.
Some examples of these agents include- phenolic -1,3, diketo analogs and chemically modified
curcumins. More clinical trials on humans are required to authenticate their use as host modulating
agent.

70. 70
 Semisynthetic Glycosaminoglycan Ether (SAGE)- Their mechanism of action is based on their ability to
reduce the impact of advanced glycation end products, thus, reducing the proinflammatory mediators of
disease. Human trials still need to be investigated.
 Stem cells in host modulation therapy- use of stem cells to regenerate lost tissues is being extensively
studied presently.

71. 4 D approach to ameliorate Periodontitis
Jain P, Mirza MA, Iqbal Z. A 4-D approach for amelioration of periodontitis.Medical hypotheses. 2019 Dec 1;133:109392. 71

72. CONCLUDING COMMENTS
72

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