Can Systemic Diseases Co-induce (Not Just Exacerbate) Periodontitis? A Hypothetical “Two-hit” Model

ligaments), but also results in signs of periodontal destruction, including elevated MMPs in the gingiva, periodontal bone loss, and increased tooth mobility (Ramamurthy et al., 2005). As in this model and other animal models of bone and connective tissue destruction described below, no attempt was made to alter the already-present oral microflora or subgingival biofilm. In addition to this line of evidence supporting our "two-hit" hypothesis, treatment of either the AA rat model, or an endotoxin-induced CDP rat model, with MMP-inhibitor drugs (e.g., non-antimicrobial chemically modified tetracyclines [CMTs]) suppressed joint destruction and periodontal breakdown, respectively, presumably by blocking the "2nd hit" but not the microbial products (Greenwald et al., 1992; Golub et al., 1998; Ramamurthy et al., 2002). Evidence from human studies also suggests that both adult rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) can increase the incidence of periodontitis (Kasser et al., 1997; Miranda et al., 2003). One possible link between the systemic and local diseases includes systemic osteoporosis as a complication of arthritis (Greenwald and Kirkwood, 1999), which may potentiate accelerated periodontal bone loss (Payne et al., 1999). Another link is the elevated levels of inflammatory mediators, both locally in the diseased synovium and systemically in the circulation. In fact, elevated levels of proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)have been observed in the serum of RA and JIA patients (Vreugdenhil et al., 1990; Yilmaz et al., 2001). These cytokines are thought to stimulate resident cells in the synovium and the periodontium to produce MMPs mediating connective tissue destruction, and to induce the differentiation and activity of osteoclasts to destroy bone (Lotz et al., 1995; McGee et al., 1998). One such cytokine in particular, TNF, also promotes bone resorption: (i) by up-regulating inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) (Soory, 2002); and (ii) by modulating the receptor activator of nuclear factor B (NF B) ligand (RANKL) in osteoblasts, and its antagonist osteoprotegerin (OPG), thus altering the RANKL/OPG ratio, which enhances osteoclast activity (Hofbauer et al., 2000; Haynes, 2004). We are not suggesting that circulating (serum levels of) proinflammatory cytokines by themselves are having a proportionately direct effect on synovial or periodontal target cells to produce MMPs, NO, or RANKL, since their local concentrations in RA and CDP are thousands of times higher than those in serum (Miranda et al., 2005). However, elevated The connection between systemic diseases and chronic destructive periodontitis (CDP) has received increasing attention in recent years. A major unanswered question is how disease in one part of the body (e.g., the joints and skeletal tissues) can transmit signals to the periodontium to enhance or, as we hypothesize in this report, to co-induce CDP. The inflammatory mediators and effector molecules described below, carried by the circulation, are likely conduits. The purpose of this paper is to explore a proposed "two-hit" model of CDP (Fig.), by interpreting the results of experiments with animal models and supported by evidence from human clinical studies. This model conceptualizes how boneand connectivetissue-destructive diseases in one location (e.g., the joints in patients with rheumatoid arthritis, the skeletal system during post-menopausal osteoporosis, and others) may communicate with the tissues in the periodontium (the 2nd "hit"), together with the microbial products (e.g., endotoxin) generated by the subgingival biofilm (the 1st "hit"), to co-induce periodontitis (Fig.). A similar "two-hit" model has recently been proposed to explain the pathogenesis of acute lung injury during acute respiratory distress syndrome (ARDS), mediated by essentially the same inflammatory mediators and effector molecules as proposed in this paper (Carney et al., 1999; Steinberg et al., 2005a). Our hypothesis and model are further supported by a wealth of evidence, accumulated over the past several decades, suggesting that inhibitors of these mediators and effector molecules (particularly pleotropic MMP-inhibitor drugs, notably the non-antimicrobial formulations of tetracycline compounds) can reduce the severity of several of these systemic diseases (e.g., ARDS, rheumatoid arthritis, post-menopausal osteoporosis), as well as periodontitis, in experimental animals and, in some cases, in humans as well (Golub et al., 1998, 1999; Payne and Reinhardt, 1998; Carney et al., 1999; Elliott et al., 2003; Brandt et al., 2005; Steinberg et al., 2005b). Addressing the first example of this hypothesis, it has recently been demonstrated that inducing adjuvant arthritis (AA) in the rat not only produces systemic inflammatory multi-joint destruction, including dramatic elevations of host-derived matrix metalloproteinases (MMPs) such as collagenase and gelatinase