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Subsequently, in the 1980s, host\u2010response mechanisms were identified as the mediators of the destruction of the collagen\u2010rich 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\u2010modulation 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\u2010derived matrix metalloproteinases (notably, the collagenases, gelatinases, macrophage metalloelastase), and by mechanisms unrelated to the antimicrobial properties of these medications; and (2) that nonsteroidal anti\u2010inflammatory drugs, such as flurbiprofen, again by nonantimicrobial mechanisms, could reduce the severity of periodontitis (however, the adverse effects of long\u2010term therapy precluded their development as safe and effective host\u2010modulatory agents). Additional mechanistic studies resulted in the development of novel nonantimicrobial formulations (Periostat\u00ae [now generic] and Oracea\u00ae) and compositions of tetracyclines (notably chemically modified tetracycline\u20103) as host\u2010modulator 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\u2010binding active site in the tetraphenolic chemically modified tetracycline molecules drove the development of a new category of matrix metalloproteinase\u2010inhibitor compounds, with a similar active site,\u00a0the 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\u2010modulation 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\u2010too\u2010common \"inflammatory\/collagenolytic\" disease; and Oracea\u00ae is now commonly prescribed for inflammatory dermatologic diseases.<\/jats:p>","DOI":"10.1111\/prd.12315","type":"journal-article","created":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T05:57:25Z","timestamp":1576648645000},"page":"186-204","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":171,"title":["Periodontal therapeutics: Current host\u2010modulation agents and future directions"],"prefix":"10.1111","volume":"82","author":[{"given":"Lorne M.","family":"Golub","sequence":"first","affiliation":[{"name":"Department of Oral Biology &amp; Pathology School of Dental Medicine Stony Brook University Stony Brook New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsi\u2010Ming","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Oral Biology &amp; Pathology School of Dental Medicine Stony Brook University Stony Brook New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.14219\/jada.archive.1994.0261"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/08959374980120010501"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345760550060701"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2795(78)90477-4"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.1983.tb00388.x"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.1984.tb01334.x"},{"key":"e_1_2_11_8_1","first-page":"111","article-title":"The nonantimicrobial properties of tetracycline for the treatment of periodontal disease","volume":"2","author":"Vernillo AT","year":"1994","journal-title":"Curr Opin Periodontol"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-051X.2005.00840.x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2004.75.3.441"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2010.12.003"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2008.080174"},{"key":"e_1_2_11_13_1","first-page":"1","article-title":"A \u201cpoint\u2010by\u2010point\u201d statement on periodontal host\u2010modulation therapy: SAFETY FIRST!","author":"Golub LM","year":"2018","journal-title":"Oral Health"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3402\/jom.v4i0.19227"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-051X.2004.00558.x"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2008.080173"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2014.130701"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2017.04.006"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.1989.60.9.485"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2294"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2008.080231"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13479"},{"issue":"2","key":"e_1_2_11_23_1","first-page":"S256","article-title":"Host modulation by therapeutic agents","volume":"4","author":"Elavarasu S","year":"2012","journal-title":"J Pharm Bioallied Sci"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890600800103"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/idj.12221"},{"key":"e_1_2_11_26_1","article-title":"Effects of short\u2010term COL\u20103 on local biomarkers of periodontitis","volume":"87","author":"Ryan ME","year":"2008","journal-title":"J Dent Res"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.04.2614"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/959471"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/jre.12381"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-017-0587-4"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712802884295"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712802884240"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/5782904"},{"issue":"2","key":"e_1_2_11_34_1","first-page":"97","article-title":"Special issue (part 1). 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