With the recognition in the 1960s and 1970s of the periodontopathic importance of the microbial biofilm and its specific anaerobic microorganisms,
periodontitis was treated as an
infectious disease (more recently, as a
dysbiosis). Subsequently, in the 1980s, host-response mechanisms were identified as the mediators of the destruction of the
collagen-rich periodontal tissues (gingiva, periodontal ligament, alveolar bone), and the periodontopathogens were now regarded as the "trigger" of the inflammatory/collagenolytic response that characterizes actively destructive
periodontitis. Also at this time a new pharmacologic strategy emerged, entitled "host-modulation
therapy", based on 2 major findings: (1) that the ability of
tetracycline antibiotics to inhibit periodontal breakdown was due (in large part) to their previously unrecognized ability to inhibit the host-derived
matrix metalloproteinases (notably, the
collagenases,
gelatinases,
macrophage metalloelastase), and by mechanisms unrelated to the antimicrobial properties of these medications; and (2) that nonsteroidal anti-inflammatory drugs, such as
flurbiprofen, again by nonantimicrobial mechanisms, could reduce the severity of
periodontitis (however, the adverse effects of long-term
therapy precluded their development as safe and effective host-modulatory agents). Additional mechanistic studies resulted in the development of novel nonantimicrobial formulations (Periostat® [now generic] and Oracea®) and compositions of
tetracyclines (notably chemically modified
tetracycline-3) as host-modulator drugs for
periodontitis,
arthritis, cardiovascular and
pulmonary diseases,
cancer, and, more recently, for local and systemic bone loss in postmenopausal women. Identification of the
cation-binding active site in the tetraphenolic chemically modified
tetracycline molecules drove the development of a new category of
matrix metalloproteinase-inhibitor compounds, with a similar active site, the biphenolic chemically modified curcumins. A lead compound, chemically modified
curcumin 2.24, has demonstrated safety and efficacy in vitro, in cell culture, and in vivo in mouse, rat, rabbit, and dog models of disease. In conclusion, novel host-modulation compounds have shown significant promise as adjuncts to traditional local
therapy in the clinical management of
periodontal disease; appear to reduce systemic complications of this all-too-common "inflammatory/collagenolytic" disease; and Oracea® is now commonly prescribed for inflammatory dermatologic diseases.