Host modulation by therapeutic agents.

Periodontal disease susceptible group present advanced periodontal breakdown even though they achieve a high standard of oral hygiene. Various destructive enzymes and inflammatory mediators are involved in destruction. These are elevated in case of periodontal destruction. Host modulation aims at bringing these enzymes and mediators to normal level. Doxycycline, nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, nitrous oxide (NO) synthase inhibitors, recombinant human interleukin-11 (rhIL-11), omega-3 fatty acid, mouse anti-human interleukin-6 receptor antibody (MRA), mitogen-activated protein kinase (MAPK) inhibitors, nuclear factor-kappa B (NF-kb) inhibitors, osteoprotegerin, and tumor necrosis factor antagonist (TNF-α) are some of the therapeutic agents that have host modulation properties.

Host modulation is a new term incorporated in our dental vocabulary. Host can be defined as “the organism from which a parasite obtains its nourishment.” Modulation is defined as “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). In diseases of the periodontium that are initiated by bacteria, the “host” clearly is the individual who harbors these pathogens. Host modulation with chemotherapeutic therapy or drugs is a promising new adjunctive therapeutic option for the management of periodontal diseases.

Concept of Host Modulation

Not all individuals develop periodontitis. Development of gingivitis seems to be dependent on host response. Plaque bacteria initiate the disease and bacterial antigens cross the junctional epithelium and drive the inflammatory process. Bacteria are essential for periodontitis to occur, but they are insufficient to cause the disease alone. For periodontitis to develop, a susceptible host is also required. Page et al.[1] in 1997 reported that the majority of periodontal breakdown (bone loss, attachment loss) is caused by host destructive enzymes like matrix metalloproteinases (MMPs) and inflammatory mediators (prostaglandins, interleukins) that occur as a part of inflammatory response. Paradoxically, the inflammatory response, which is essentially protective in design, is responsible for much of the breakdown of the soft and hard periodontal tissue. Page et al.[2] in 1999 reported that periodontal disease is characterized by high concentrations of MMPs, cytokines, and prostanoids in the periodontal tissue. The purpose of host modulation therapy is to restore the balance of proinflammatory or destructive mediators and anti-inflammatory or protective mediators to that seen in healthy individuals.

Agents Used in Host Modulation

Three categories of host-modulating agents have been investigated in the periodontal therapy:

antiproteinases (represented by tetracyclines),

anti-inflammatory drugs, and

bone-sparing drugs (represented by anti-resorptive agents such as bisphosphonates).

Subantimicrobial-dose doxycline

In 1985, Golub et al.[3] reported that tetracyclines have anti-collagenolytic activity and were proposed as a host-modulating agent for periodontal treatment. According to the findings of Burns et al.[4] (1989), doxycycline was the most potent tetracycline in the inhibition of collagenolytic activities. Golub et al.[5] in 1990 reported that this property of doxycycline provided the pharmacological rationale for the use of a low or subantimicrobial dose of doxycycline, which was shown to be efficient in inhibiting mammalian collagenase activity without developing antibiotic resistance.

Mechanism of action

to Birkedal-Hansen[6] (1989), in addition to antibiotic properties, doxycyline has the ability to downregulate MMPs, a family of the zinc-dependent enzymes that are capable of degrading extracellular matrix molecules, including collagen. MMPs are secreted by fibroblasts, keratinocytes, macrophages, Polymorpho neutrophil (PMNs), and endothelial cells. Excessive amounts of MMPs are produced in inflamed periodontal tissue. These MMPs cause breakdown of the connective tissue. Doxycyline downregulates MMPs by various mechanisms:

In junctional epithelium[7]

Inhibition of production of epithelial-derived MMPs by inhibiting cellular expression and synthesis

In connective tissue[7]

Direct inhibition of active MMPs by cation chelation

Inhibition of oxidative activation of latent MMPs

Downregulates the expression of key inflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, as well as prostaglandin E2 (PGE2)

Scavenges and inhibits production of reactive oxygen species (ROS) produced by PMNs (e.g. HOCl, which activates latent MMPs)

Inhibition of MMPs and ROS protects α1 proteinase inhibitor (α1-PI), thereby indirectly reducing tissue proteinase activity

Stimulates fibroblast collagen production

Alveolar bone[7]

Reduces osteoclast activity and bone resorption

Blocks osteoclast MMPs

Stimulates osteoblast activity and bone formation

Nonsteroidal anti-inflammatory drugs

According to Grenier et al.[8] (2002), nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins, including PGE2, which is produced by neutrophils, macrophages, fibroblasts, and gingival epithelial cells in response to the presence of lipopolysaccharide (LPS). PGE2 has been observed to be increased in periodontal disease compared with the level in healthy patients. Grossi et al.[9] (1997) reported that PGE2 also inhibits fibroblast function and has inhibitory effects on the immune response. NSAIDs inhibit prostaglandins and thus reduce tissue inflammation. They are used to treat pain, acute inflammation, and a variety of chronic inflammatory conditions. NSAIDs include the following:

Salicylates (e.g. aspirin)

Indomethacin

Propionic acid derivatives (e.g. ibuprofen, flurbiprofen, naproxen)

Administration of NSAIDs for 3 years has shown significant reduction in alveolar bone destruction [Figure 1].

Figure 1

Potential therapeutic strategies to treat bone resorption: Agents that block the differentiation or activity of osteoclasts are potential therapeutic agents. Osteoprotegerin (OPG) inhibits the differentiation of osteoclasts through its action as a decoy receptor that blocks receptor activator of nuclear factor-kappa B (NF-kB) ligand (RANKL) and RANK juxtacrine interaction. NSAIDs and other anti-inflammatory molecules [including p38 mitogen-activated protein kinase (MAPK) inhibitors, c-jun N-terminal kinase (JNK) inhibitors, and NF-kB inhibitors] can inhibit the formation of hematoprogenitor cells to pre-osteoclasts. Antibodies to RANKL can also block this interaction. MMP inhibitors reduce the protease degradation of the organic matrix, and anti-integrins block the initial osteoclast adhesion to the matrix. IL = interleukin; LPS = lipopolysaccharide; M-CSF = macrophage colony-stimulating factor; sRANKL = soluble RANKL; TNFα = tumor necrosis factor-α; TNFsRc = TNF soluble receptor

Disadvantages

Gastrointestinal problems

Hemorrhage (decreased platelet aggregation)

Renal and hepatic impairment

Bone loss accelerates when NSAIDs are stopped abruptly (rebound effect)

Alternative drug (cyclooxygenase 2 inhibitors)

Bezzere et al.[10] in 1993 reported that cyclooxygenase 2 (COX2) is induced after stimulation by cytokines, growth factors, and LPS, and results in elevated amount of prostaglandin. Inhibition of COX2 by selective COX2 inhibitors offered the prospect of reducing periodontal inflammation without the side effects of using long-term non-selective NSAIDs. COX2 slowed down alveolar bone loss.

Bisphosphonates

According to El-Shinnawi et al.[11] (2003), bisphosphonates are bone seeking agents that inhibit bone resorption by disrupting osteoclast activity. They interfere with osteoblast metabolism and secretion of lysosomal enzymes. More recent evidence has suggested that bisphosphonates also possess anticollagenase properties. In human studies, these agents resulted in enhanced alveolar bone status and density.

Inhibit bone calcification

Induce changes in white blood cell count

Avascular necrosis of the jaws

Newer Agents for Host Modulation

The improvement of knowledge and better elucidation of the host mechanisms which participate in the pathogenesis of the periodontal disease have resulted in the proposal of new agents aimed at host modulation through the inhibition of inflammatory mediators. Preclinical studies in an animal experimental model of periodontitis have shown significant local benefits and provide support for the development of new drugs to periodontal treatment in the future. These studies are briefly discussed below.

NO synthase inhibitors

Lietao et al.[12] (2005) reported that nitric oxide synthase (NOS) inhibitors have protective effects against bone resorption and inflammatory process in ligature-induced 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. 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.

Recombinant human interleukin-11

According to Trepicchion et al.[13] in 1995, IL-11 was shown to have anti-inflammatory effects by inhibition of TNF-α and other proinflammatory cytokines. Moreover, Leng et al. in 1995 observed that it indirectly minimizes tissue injury through stimulation of tissue inhibitor of metalloproteinase-1 (TIMP-1). Based on these previous studies, Martuscelli et al. in 2000 investigated the ability of recombinant human IL-11 (rhIL-11) to reduce periodontal disease progression in dogs with ligature-induced periodontitis. Significant reduction in the rate of clinical attachment and radiographic bone loss were observed after an 8-week period of rhIL-11 administration twice a week.[14] The authors suggested that new studies should be conducted toward the therapeutic use of rhIL-11 in periodontal treatment.

Omega-3 fatty acid

Recently, Vardar et al.[15] in 2005 evaluated the use of omega-3 fatty acids with the purpose of blocking arachidonic acid cascade in induced periodontal disease in rats. This would result in the inhibition of production of not only prostanoids derived from the COX pathway but also leukotrienes derived from the lipooxygenase pathway. The authors based their therapeutic approach on two facts: first, leukotriene B4, a mediator formed from arachidonic acid via lipooxygenase, plays a significant role in alveolar bone resorption and second, inhibition of COX with NSAIDs would result in the accumulation of arachidonic acid, which could be metabolized by the lipooxygenase pathway and result in continuous bone loss. The authors also combined omega-3 fatty acid with celecoxib, looking for a synergism of the anti-inflammatory effects of these two agents. The associated therapy resulted in significant superior reductions on periodontal tissue levels of prostaglandins, leukotriene B4, and platelet-activating factor, which is also a proinflammatory mediator. No significant effect was observed on bone loss, which was related to the short period of evaluation [Figure 1].

Mouse anti-human interleukin-6 receptor antibody

Hyper production of IL-6 is observed in the rheumatoid arthritis patients and the serum level of IL-6 is closely related to disease activity. IL-6 is a pleiotropic cytokine and its hyper functions explain most of the clinical symptoms in rheumatoid arthritis. MRA is a humanized antibody from a mouse anti-human IL-6 receptor antibody, which can be administered repeatedly because of its low antigenicity in humans. MRA inhibits IL-6 function by blocking IL-6 binding to the IL-6 receptor, resulting in the prevention of the development of collagen-inducing arthritis in cynomolgus monkeys whose Interluekin-6 receptor cross-reacts with MRA. This evidence suggests that MRA has anti-arthritic effects.[16]

Disruption of Cell Signaling Pathway

Strategies for preventing cell activation seek to inhibit the intracellular transduction of signals produced when ligands bind to their membrane receptors. Inhibition of signal transduction pathways would be expected to abolish both cell activation by cytokines or other stimuli and the production of proinflammatory cytokines. Cytokines and bacterial components activate many signal transduction pathways. Signal transduction pathways closely involved in inflammation include the mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol-3 protein kinase (PI3) pathway, janus kinase-signal transducer and activator of transcription (Jak-STAT), and NF-kB. In addition, other signal transduction pathways are of fundamental importance in inflammation, such as those involving immunoreceptors (integrins, selectins), G-protein coupled receptors (chemokine receptors), and steroid hormone receptors. Therapeutic strategies have been directed toward many of these major signaling pathways, notably MAPK and NF-kB, which are discussed below.

MAPK inhibitors

Inhibit LPS-induced MMP, cytokine (IL-1b, TNF-α, IL-6, IL-8), and prostaglandin expression.[17]

NF-kB family inhibitors

Inhibit NF-kB–dependent expression (IL-1, TNF-α, IL-6, IL-8), MMPs, IFN-c, and others [Figure 1].[18]

Disruption of the RANKL/RANK/Osteoprotegerin Axis

The RANKL/RANK interaction is responsible for differentiation and maturation of osteoclast precursor cells to activate osteoclasts. Osteoprotegerin acts as a decoy receptor, expressed by osteoblastic cells, which binds to RANKL and inhibits osteoclast development.[19] Several studies have shown the opposite effect of RANKL and osteoprotegerin in bone modulation.

Tumor necrosis factor antagonist

TNF-α, an inflammatory cytokine that is released by activated monocytes, macrophages, and T lymphocytes, promotes inflammatory responses that are important in the pathogenesis of rheumatoid arthritis and periodontal diseases. TNF-α binds to two receptors that are expressed by a variety of cells: the type 1 TNF receptor and the type 2 receptor. Activation of TNF-R1 upregulates the inflammatory response, while TNF-R2 appears to dampen the response. Blocking of TNF pathways offers significant potential in blocking disease progression.[20]

Conclusion

This review has sought to provide mechanistic overviews and clinical applications on the use of host modulatory therapeutic regimens for periodontal disease management. MMP inhibitors, such as low-dose formulations of doxycycline, have been used in combination with scaling and root planing or surgical therapy. Encouraging results have been shown using soluble antagonists of TNF and IL-1 delivered locally to periodontal tissues in non-human primates, as well as more recent evidence has been given using gene therapy vectors to provide a longer-term delivery of TNF receptor antagonists at the periodontium. In addition, the use of lipoxins has demonstrated significant potential in the management of the host response to periodontitis. Pharmacological inhibitors of NF-kB and MAPK pathways are actively being developed to manage rheumatoid arthritis and inflammatory bone diseases. Using this novel strategy, inflammatory mediators, including proinflammatory cytokines (IL-1, TNF, IL-6), MMPs, and others, would be inhibited at the level of cell signaling pathways required for transcription factor activation necessary for inflammatory gene expression or mRNA stability. These therapies may provide the next wave of disease-specific chemotherapeutics to manage chronic periodontitis.