Host modulation therapy: An indispensable part of perioceutics

Abstract

Traditionally, only antimicrobials have been used as the chemotherapeutic modality for the treatment of periodontitis. Though bacteria are the primary etiologic factors of periodontal diseases, yet the extent and severity of tissue destruction seen in periodontitis is determined by the host immuno-inflammatory response to these bacteria. This increasing awareness and knowledge of the host-microbial interaction in periodontal pathogenesis has presented the opportunity for exploring new therapeutic strategies for periodontitis by means of targeting host response via host-modulating agents. This has lead to the emergence of the field of “Perioceutics” i.e. the use of parmacotherapeutic agents including antimicrobial therapy as well as host modulatory therapy for the management of periodontitis. These host-modulating agents used as an adjunct tip the balance between periodontal health and disease progression in the direction of a healing response. In this article the host-modulating role of various systemically and locally delivered perioceutic agents will be reviewed.

INTRODUCTION

Although microbial plaque has been recognized as the primary etiologic agent for the development of periodontal disease,[1] yet, the severity, pattern and progression of this disease cannot be solely explained by the amount of plaque present.[2] Periodontal pathogens present within the microbial biofilms initiate the periodontal disease by producing harmful by-products and enzymes (e.g. hyaluronidases, collagenases, proteases) that break down extracellular matrices such as collagen, as well as host cell membranes, in order to produce nutrients for their growth and possibly subsequent tissue invasion.[3] This results in a host immune-inflammatory response in the periodontal tissues characterized by the production of inflammatory cytokines [e.g. interleukins (IL), tumor necrosis factor-α (TNF-α), prostanoids (e.g. prostaglandin E2) and enzymes [including the matrix metalloproteinases (MMPs)].[4,5] The level of these inflammatory mediators in the periodontal tissues is usually balanced by the anti-inflammatory cytokines and enzymes of the host immune system which ultimately functions to eliminate microbial pathogens and protect the host.[3,4] However, an improper or exuberate immune response in certain individuals directly leads toward overproduction of destructive enzymes and inflammatory mediators.[3] This immune-inflammatory response that develops in the periodontal tissues following chronic exposure to bacterial plaque largely determines the susceptibility of individuals to periodontal disease.[4] The variability in the host response also results from environmental and acquired risk factors which can accentuate the host inflammatory response[6] and create an imbalance between the pro-inflammatory and anti-inflammatory activities in the periodontal tissues that result in the tissue destruction.[4] The host immune-inflammatory response against bacterial plaque can thus be viewed as a “dual-edged sword,” i.e. the response is protective by intent, yet in susceptible patients who exhibit exaggerated inflammatory response to plaque, it ultimately is responsible for perpetuating destruction of periodontium.[3] This shift in paradigms, with emphasis on host response, has led to the development of host modulatory therapies (HMT) which can improve therapeutic outcomes, slow the progression of disease, allow for more predictable management of patients, and possibly even work as preventive agents against the development of periodontitis.[7,8] The concept of host modulation was first introduced to dentistry by Williams in 1990[9] and Golub et al. in 1992[10] and later on expanded by many researchers. The rationale behind this approach is to aid the host in its fight against infectious agents by supplementing the natural inherent defence mechanisms or to modify its response by changing the course of inflammatory systems.[11] The purpose of host modulatory agents, which is an imperative part of perioceutic, is to restore balance between, on the one hand, pro-inflammatory mediators and destructive enzymes, and on the other hand, anti-inflammatory mediators and enzyme inhibitors. The use of perioceutics becomes obligatory when patients are unable to effectively reduce risks such as the risk presented by the patient's genetics, smokers who are unable to quit the habit, patients who are unable to maintain adequate oral hygiene, the inability to reduce stress, diabetics who are poorly controlled despite the physician's best efforts, and the inability or unwillingness of the physician to alter medications of the patients. The term perioceutic (periodontal + therapeutic) was first introduced by Heska Corporation (Fort Collins, CO). In 1998, this corporation filed to protect the “perioceutic” trademark for labeling periodontal therapeutic gels especially for use in veterinary field, but in 2000 this trademark was abandoned.[12,13] However, this term is currently being used to address the pharmacotherapeutic agents specifically developed to better manage periodontitis.[14,15] This field of “perioceutics,” that includes antimicrobial therapy and host modulatory therapy, to produce beneficial changes in the microflora and host response, respectively, has emerged as a vital aid in the management of susceptible patients who develop periodontal disease.[16]

Compared to other therapeutic modalities employed against infection, host response modulation, potentially is non-invasive, has fewer side-effects, and does not require complicated application method.[17,18] This article highlights various host modulatory therapeutic agents for the treatment and management of periodontal diseases, which are an indispensable part of perioceutics and are used as an adjunct to the traditional periodontal therapies.

HOST MODULATORY THERAPY

HMT includes systemically or locally delivered pharmaceuticals that are prescribed as adjuncts to other forms of periodontal treatment.[4]

Systemically administered HMT

Host modulating agents acting against MMPs

MMPs endopeptidases which are secreted by a variety of host cells, play key roles in the degradation of the extracellular matrix, basement membrane and modify the action of cytokines as well as activation of osteoclasts.[19] During active periodontal diseases, microbial attack leads to excessive production as well as activity of these MMPs which, if not adequately controlled by the endogenous metalloproteinases inhibitors, results in enormous tissue destruction. To impede this destruction of host tissues synthetic inhibitors of MMP as host modulating agents have been developed which generally contain a chelating group, inhibiting MMPs by binding to the catalytic zinc atom at its active site. Though numerous MMP inhibitors have been investigated, only tetracycline based host modulating agent, i.e. SDD – sub-antimicrobial dose of doxycycline (Doxycycline hyclate 20 mg; Periostat, CollaGenex, Pharmaceuticals Newton PA) has been approved by Food and drug administration (FDA) to be used as an adjunct to periodontal treatment.[20] A typical prescription for Periostat (20 mg doxycycline tablets) is for at least 3 months (180 tablets, 1 tablet twice a day until complete), and refills may be provided for longer courses of therapy.[16]

Tetracycline analogues as host modulating agents

Tetracycline with antibiotic activity consists of a tetracyclic naphthacene carboxamide ring system having a dimethylamine group at carbon 4 (C4) in ring “A” which is responsible for its antibacterial property.[21] However, about 3 decades ago, Golub et al. discovered that tetracyclines and its analog have the unexpected ability to inhibit MMPs, by mechanisms unrelated to its antibacterial properties.[22,23]

Golub and McNamara et al. synthesized a chemically modified tetracycline (CMT) by removing the dimethylamino group from the carbon-4 position of the “A” ring, resulting in the 4-de dimethylaminotetracycline, i.e. CMT, which eliminated the drug's antimicrobial efficacy but did not reduce the ability of the drug to block the activity of collagenases.[24,25]

Recently, bisphosphonates which are generally bone-sparing agents have been found to inhibit MMPs. Bisphosphonates will be discussed later in this article.

Host modulating agents acting against arachidonic acid metabolites

Free arachidonic acid (AA) is produced in the hosts when phospholipase A2 acts on the phospholipids present in plasma membranes of the cells which can then be metabolized to produce prostaglandins via the cyclooxygenase (COX) pathway as well as leukotrienes via the lipoxygenase (LOX) pathway. Recently, Dybvig also validated that prostaglandins are an important mediator of bone loss in periodontitis.[26] Non-steroidal anti-inflammatory (NSAIDs) drugs block the activity of both cyclooxygenase isozymes (COX- 1 and -2) and many authors have demonstrated the role of NSAIDs like flurbiprofen,[27] indomethacin,[28] and naproxen,[29] in inhibiting gingivitis and progression of periodontitis. Lipoxins (LX) which are generated endogenously late in inflammation via cell-cell interaction when a second lipoxygenase (e.g. 5-LOX) interacts with a lipoxygenase product (e.g. hydroxyeicosatetraenoic acid) generated earlier from archidonic acid,[30] also possess both anti-inflammatory and pro-resolving potential which have been summarized by Serhan et al. as reduction of neutrophil infiltration and recruitment, blocking cytokines and reactive oxygen species generation, thereby preventing connective tissue and bone loss.[31] Hence, LXs can be targets for HMT against periodontitis.

Lipid - inflammatory mediators as targets for HMT

Among the other endogenous chemical mediators resolvins, protectins, and newly identified maresins have shown to mediate resolution and counter-regulate excessive acute inflammation.[32] These are biosynthesized from precursors like omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) via sequential steps involving lipoxygenases (LOX), and cyclooxygenases (COX).[31,33,34] The role of these endogenous chemical mediators is similar to that of lipoxins, i.e. inhibition of neutrophil recruitment etc.[32,33] These stereoselective players counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution.[35] Thus, designing pharmacological mimetics of naturally occurring pro-resolving mediators offers exciting new targets for drug design,[36] especially for host modulation therapy.

Host modulating agents acting against cytokines

Pro-inflammatory (e.g. IL-1α, IL-1β, IL-6, TNF-α, IFN-γ etc) and anti-inflammatory cytokines (IL-4, IL-10 etc) hold a great potential for controlling the adverse effects of the host immune response, consequently HMT against cytokines (cytokine therapy) may prove to be an effective strategy for treating periodontal diseases.[37]

These therapies aim at:

– Antagonizing the pro-inflammatory cytokines via

• Cytokine receptor antagonist: Binds to the receptor present on the target cell and prevents the cytokine from binding to the target cell. E.g. interleukin-1 receptor antagonist (IL-1ra) which is commercially available as Kineret (Anakinra, Amgen)[38,39]

• Anti-cytokine antibodies: Some of the anticytokine antibodies currently available are:

• Anti TNF-α antibody: Adalimumab (Humira, manufacturered by Abbott Laboratories), Cetrolizumab pegol (Cimzea, manufacturered by Union chimique belge), Golimumab (Simponi, manufacturered by Centocor) etc.

• Anti IL-6 antibody: Tocilizumab (RoActemra, manufacturered by Roche)

• Anti IL-15 antibody: AMG714 (AMG714, manufacturerd by Novartis)

• Anti IL-12 and IL-23 antibody: Ustekinumab (Stelara, manufacturered by Centacor)

• Anti IL-17 antibody: AIN457 (AIN457, manufacturered by Novartis)[38]

• Soluble cytokine receptors: Binds to the cytokines in solution and prevents signaling. e.g. sIL-1R, sTNF-R, sIL-6R are the soluble receptors against IL-1β, TNF-α and IL-6, respectively[39]

– Disrupting inflammatory cell-signalling pathways

To inhibit the production of pro-inflammatory cytokines and/or stimulate anti-inflammatory cytokine production. Cell-signalling pathways like Mitogen Activated Protein Kinase (MAPK), Nuclear Factor-Kappa B (NFκB), Janus kinase/signal transducers and activators of transcription (JAK/STAT) and Receptor activator of nuclear factor-kappa B (Rank)-Receptor activator of nuclear factor-kappa B ligand (Rankl)-Osteoprotegerin (OPG) pathways are dependent on a number of signaling-intermediate molecules for its uninterrupted functioning. Targeting these pathways or the intermediate signaling molecules for their blockade with HMT may be more effective than targeting specific cytokines.[6] It has also been seen that the activity of cytokines is also controlled by the suppressors of cytokine signaling (SOCS - SOCS-1, -2 and -3) messenger ribonucleic acid (mRNA), which when expressed, down-regulate the signal transduction and inflammatory cytokine production as a part of an inhibitory feedback loop.[40,41] The exploration of these molecules further open up many new possibilities for modulating host response. Based on the clinical data Souza et al. have listed some of the inhibitors targeting these signalling pathways that have been manufactured and have demonstrated anti-inflammatory activity, these are: SD-282, SC-409, SB (SmithKline Beecham) -242235, AW-814141, BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA) and VX-702 that act as p38 inhibitors; SP600125 (Celgene Corporation, San Diego, California, USA) as c-Jun N-terminal kinases (JNK) inhibitor; FR180204 as Extracellular-Signal-Regulated Kinases (ERK) inhibitor; BMS (Bristol-Myers Squibb)-345541 as NFκB inhibitor; CP-690550 (Pfizer) as JK3 inhibitor.[6] Lima et al. (2004) further demonstrated the protective role of pentoxifylline (PTX), a methylxanthine derivative, in experimental periodontitis as a inhibitor of cytokine synthesis, mainly tumor necrosis factor (TNF).[42] Likewise, a number of intracellular signaling pathways involved in osteoclastogenesis, activated upon RANK-RANKL binding are blocked by osteoprotegerin (a natural inhibitor of RANKL), which acts as a decoy and blocks the binding of RANKL to RANK. Moreover the protective role of OPG has also been supported by the association of disease severity with an increase in RANKL ⁄ osteoprotegerin ratio at periodontally inflamed sites.[43] Thus, modulation of the RANKL ⁄ RANK ⁄ osteoprotegerin axis via pharmacotherapeutic agents may lead to an increase in osteoprotegerin and a decrease in RANKL to a level consistent with an equilibrium state between bone formation and bone destruction.[38] Jin et al. (2007) demonstrated that systemic delivery of OPG-Fc fusion protein inhibits alveolar bone resorption in experimental periodontitis, supporting the fact that RANKL inhibition may represent an important therapeutic strategy for the prevention of progressive alveolar bone loss.[44] Studies to date have indicated that RANKL inhibitors, such as a fully human monoclonal antibody that specifically targets RANKL currently available as denosumab (Denosumab, Amgen) can lead to increased bone mineral density and decreased bone resorption.[38]

– Recombinant anti-inflammatory cytokine administration

Martuscelli et al. demonstrated that subcutaneous injections of recombinant human IL-11 (rh IL-11: anti-inflammatory cytokine) were able to slow the progression of attachment and radiographic alveolar bone loss in a ligature-induced beagle dog model.[45]

Host modulating agents acting against bone resorption

Bisphosphonates (BPs) are pyrophosphate analogs that can suppress osteoclastic bone resorption[46] Bisphosphonates are known to bind to hydroxyapatite crystals and prevent their dissolution in addition to increasing osteoblast differentiation and inhibiting osteoclast activation.[4] Giannobile WV has summarized and categorized the bone-specific actions of bisphosphonates at the tissue level (decrease bone turnover due to inhibition of bone resorption, decrease the number of new bone multicellular units resulting in a net positive whole body bone balance) and at cellular level (decrease osteoclast recruitment, osteoclast adhesion, depth of resorption site and release of cytokines by macrophages along with an increase in osteoclast apoptosis and osteoblast differentiation and number).[5,47] FDA has approved the use of these drugs orally or intravenously in the management of Paget's disease, osteoporosis, and bone metastases.[48] Based on its bone-sparing properties there exists a possible use for bisphosphonates in the management of periodontal diseases as well. Shoji et al. in 1995 demonstrated that systemic administration of a bisphosphonate could prevent alveolar bone resorption in rats with experimental periodontitis.[49]

Furthermore, anti-integrins can also block the initial osteoclast adhesion to the matrix and prevent bone resorption.[3] Based on the well demonstrated role of estrogen on excessive bone resorption as well as its lack in the post-menopausal osteoporosis affecting the remodeling of the bone tissue in such a way that, in most patients with periodontitis the amount of bone resorbed exceeds that being formed, resulting in net bone loss, Inagaki et al. has also suggested the use of selective estrogen receptor modulators (SERM) and hormone replacement therapy (HRT) to improve the clinical outcome of periodontal disease as an adjunctive treatment to preserve periodontal bone mass.[50] Shu et al. in 2008 also demonstrated in human periodontal cells that estrogen may play a significant role in modulating periodontal tissue responses to lipo-polysaccharide, and may exert its bone-sparing effects on periodontal tissues via altering the expression of inflammatory cytokines.[51] Yet, given the potentially large number of significant side-effects associated with hormone replacement therapy, it is difficult to see this being recommended as a management strategy for periodontitis.[38]

Modulation of nitric oxide synthase

Nitric oxide is a free radical with important physiological functions of maintaining homeostasis. While homeostasis requires low nitric oxide tissue levels, pro-inflammatory stimuli such as endotoxins leads to increased expression of the inducible nitric oxide synthase enzyme (iNOS) that produces a large amount of nitric oxide (NO) and peroxynitrite, which acts beneficially for the host as a cytotoxic molecule against the invading microorganism, yet, it may also cause deleterious effects to host such as DNA damage, lipid peroxidation, protein damage, and stimulation of inflammatory cytokine release.[52,53,54] Lohinai et al. (1998) demonstrated the protective effects of mercaptoethylguanidine (MEG), which is a selective inhibitor of iNOS, against bone destruction in ligature-induced periodontitis in the rat.[55] Recently, Leitao et al. (2005) also proved that NOS inhibitors prevent alveolar bone resorption in experimental periodontitis.[56]

Other host modulatory therapies

Probiotics

Probiotics have demonstrated significant potential as therapeutic options for a variety of disease as they have been known to modulate cytokine secretion profiles, influence T-lymphocyte populations, protect against physiologic stress, and enhance intestinal epithelial cell function and antibody secretion.[57] Recently, Teughels et al. (2011) explored the use of probiotics in influencing the periodontal microbiota and periodontal health and concluded that probiotics might offer opportunities to manipulate the oral microbiota, and periodontal health by either direct microbiological interactions or by immunomodulatory interactions.[58]

Periodontal vaccines

George Hajishengallis reported that toll like receptors (TLRs) may offer novel targets for host-modulation therapy in periodontitis since manipulation of TLR signalling may contribute to control of infection or regulation of inflammation and, moreover, synthetic or natural TLR agonists could serve as novel periodontal vaccine adjuvants.[59] Yokoyama et al. in 2007 also demonstrated that egg yolk antibody against Porphyromonas gingivalis (IgY-GP) proved to be an effective immunotherapeutic agent in the treatment of periodontitis.[60] Similarly, Choi et al. reported that prior immunization of mice to Fusobacterium nucleatum modulated the host immune responses to Porphyromonas gingivalis at the humoral, cellular and molecular level.[61]

Nutrients

Nutrients, which include major extracellular antioxidants, like vitamin C, vitamin E, carotenoids, reduced glutathione and omega 3 fatty acids can also act as modulators of inflammation by scavenging free radicals as they are formed, sequestering transition metal ions and catalyzing formation of other molecules.[62] Studies have also demonstrated that cranberry juice contains molecules (A-type cranberry proanthocyanidins: AC-PACs) that inhibit MMPs, interleukin-6, interleukin-8, and prostaglandin E production by lipopolysaccharide-activated gingival fibroblasts and hence show potential of being used as a novel host-modulating agent to inhibit tissue destruction during periodontitis.[63,64]

Locally administered HMT

In addition, a number of local host modulatory agents have been investigated in clinical trials for their potential use as adjuncts to surgical procedures, not only to improve on wound healing but also to stimulate regeneration of lost bone, periodontal ligament, and cementum, restoring the complete periodontal attachment apparatus.[16]

Enamel matrix proteins

It is believed that during development of root and attachment apparatus, there is a secretory phase in which Hertwig's epithelial root sheaths secretes enamel-related matrix proteins.[65] Enamel matrix derivative is now commercially available for the treatment of periodontal defects as Emdogain^® (Biora AB, Malmö, Sweden) which has received FDA approval.[66] The basic rationale behind using Emdogain is that it will act as a tissue-healing modulator that would mimic the events that occur during root development and help stimulate periodontal regeneration.[66,67,68] Enamel matrix proteins (EMD) initiates periodontal regeneration through recruitment of cementoblasts to the root-surface and stimulates these to form root-cementum, which will thereafter secondarily lead to regeneration of periodontal fibers and alveolar bone.[69] The above mentioned actions of EMD justify its role as a host modulating agent.

Bone morphogenetic protein

Bone morphogenetic protein (BMP) guides modulation and differentiation of mesenchymal cells into bone and bone marrow cells.[70] Absorbable collagen sponge (ACS) containing recombinant human BMP-2 has been approved for clinical use in certain oral surgery procedures, including localized alveolar ridge augmentation, under the name INFUSE® Bone Graft (Medtronic, Minneapolis, MN, USA) and InductOS™ (Wyeth, Maidenhead, UK). These ACS release the protein over time in the location where it is implanted and provides a scaffold on which new bone can grow. As the graft site heals, the ACS is absorbed and replaced by bone.[71]

Platelet derived growth factor

FDA has approved Growth-factor Enhanced Matrix, GEM 21S^® (Osteohealth, Shirley, NY) which is a combination of a bioactive highly purified recombinant human PDGF-BB with an osteoconductive bone matrix.[71] Platelet derived growth factor (PDGF), as a host modulating agent can increase chemotaxis of neutrophils and monocytes, stimulate fibroblasts proliferation and extracellular matrix synthesis, increase proliferation and differentiation of endothelial cells, stimulate proliferation of mesenchymal progenitor cells and differentiation of fibroblasts.[72] Nevins et al. (2005) demonstrated that the purified rhPDGF-BB mixed with bone allograft results in robust periodontal regeneration in both Class II furcations and interproximal intrabony defects.[73]

Bisphosphonate

Role and action of BPs have already being discussed above. Due to serious side-effects of systemically administered BPs leading to osteonecrosis of the jaws (ONJ) additional studies using topically administered bisphosphonates have been carried out which have reported a significant increase in the postoperative percentage of bone-defect fill, prevention of bone resorption as well as the boosting effect of locally delivered BPs on the osteoconductive and regenerative potential of bone grafts used in periodontal therapy.[74,75,76]

NSAIDs

Role of NSAIDs as a host-modulating agent has also been discussed above. Since NSAIDs are lipophilic and are well absorbed into gingival tissues, its topical application is possible. NSAIDs that have been evaluated for topical administration include ketorolac tromethamine rinse and S-ketoprofen dentifrice,[77] piroxicam[78] and meclofenamic acid[79] in inhibiting gingivitis and progression of periodontitis.

Hypochlorous Acid and Taurine-N-Monochloramine

It has been reported that hypochlorous acid (HOCl) and taurine-N-monochloramine (TauCl) which are the end-products of the neutrophilic respiratory burst, modulate the host inflammatory response by inhibiting the production of interleukin-6, prostaglandins, and other proinflammatory substances. Thus, HOCl and TauCl, playing a crucial role in the periodontal inflammatory process offer opportunities for the development of novel host-modulating therapies for the treatment of periodontitis.[80] Recently, Lorenz et al. (2009) assessed the influence of 2 and 3% N-chlorotaurine mouth rinse on dental plaque and demonstrated that rinsing with 10 mL of the test solution two times daily for 4 days reduced the plaque vitality.[81]

Cimetidine

Cimetidine is a powerful H2-(Histamine) receptor antagonist, and hence eliminates histamine's inhibitory effects on immune response, thereby acting as a modulator of inflammation and immunity by inhibiting neutrophil chemotaxis and superoxide production, increasing cyclic adenosine monophosphate (cAMP) levels and down-regulating cytokines. Hasturk et al. (2006) provided morphological and histological evidence to prove that topically active cimetidine is a potent inhibitor of P. gingivalis-elicited periodontal inflammation and can arrest and/or prevent tissue destruction and influence cell populations present in the inflammatory cell infiltrate.[82]

SUMMARY

The improved understanding of the host-bacterial interactions and the host immuno-inflammatory response leading to periodontal tissue destruction has led to the development of HMT. Though the efficacy and usefulness of host modulating agents have been demonstrated by many clinical trials and have been approved by FDA for the management of periodontitis, yet the risk/benefit ratio relating to the use of these drugs has yet to be established. Multicenter clinical trials are necessary to fully evaluate the benefits of these agents and to weigh their usefulness against the risks associated with their long-term administration. Furthermore, continuous research in this field would also enable fabrication of individualized treatment for periodontal disease targeting inflammatory host response. The current article emphasizes the promising potential of various host-modulating agents (the most crucial component of perioceutics) in the management of periodontal diseases.