title: Human neutrophil collagenase MMP-8 in peri-implant sulcus fluid and its inhibition by clodronate.
abstract: The exact molecular mechanisms of the loosening of a dental implant are not well-known. The characteristics of implant sulci are similar to those of periodontal sulci regarding gingival crevicular fluid (GCF) and peri-implant sulcular fluid (PISF). Proteolytic enzymes, matrix metalloproteinases (MMPs), participate in peri-implant tissue remodeling. Clodronate is a well-tolerated bisphosphonate-group drug currently used in bone-resorption-related diseases in humans. The mechanisms of bisphosphonate action are not clarified. Collagenase activity in diseased PISF was significantly higher than in the clinically healthy group. Immunoblotting disclosed that diseased PISF contained increased immunoreactives MMP-8 compared with the healthy PISF. The residual latent collagenase activity in the diseased PISF was activated by gold thioglucose and inhibited completely by 100 microM of doxycycline closely resembling pure neutrophil collagenase (MMP-8). The presence of MMP-8 in diseased but not in clinically healthy PISF may prove to be a useful biochemical indicator to monitor peri-implant health and disease. Pure human neutrophil collagenase (MMP-8) and the MMP-8 present in PISF and in the GCF of both loosening implants and periodontitis-affected teeth were efficiently inhibited in vitro by clodronate (50% inhibition [IC50] was achieved by 150 microM of clodronate), an osteoactive, antiresorptive bisphosphonate. Furthermore, the new finding suggests an extended and hitherto-undescribed potential for clodronate in preventing the loosening of both implants and teeth, based on a dual beneficial effect: prevention of both bone resorption/osteolysis and of soft tissue/dental ligament destruction. Potential new therapeutic indications based on the collagenase-inhibiting effect of clodronate provide potential new therapeutic indications for a variety of diseased involving connective tissue breakdown, such as periodontal disease, arthritides, and tumor invasion.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Helsinki, Finland.
authors.forename: O
authors.initials: O
authors.lastname: Teronen
authors.forename: Y T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: C
authors.initials: C
authors.lastname: Lindqvist
authors.forename: T
authors.initials: T
authors.lastname: Salo
authors.forename: T
authors.initials: T
authors.lastname: Ingman
authors.forename: A
authors.initials: A
authors.lastname: Lauhio
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.forename: S
authors.initials: S
authors.lastname: Santavirta
authors.forename: T
authors.initials: T
authors.lastname: Sorsa
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001168:Arthritis / Q000517:prevention & control; D006051:Aurothioglucose / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D017364:Collagenases / Q000032:analysis*; D003240:Connective Tissue Diseases / Q000517:prevention & control; D015921:Dental Implants; D019232:Dental Restoration Failure; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005883:Gingival Crevicular Fluid / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D020784:Matrix Metalloproteinase 8; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D010014:Osteolysis / Q000517:prevention & control; D010510:Periodontal Diseases / Q000517:prevention & control; D010513:Periodontal Ligament / Q000187:drug effects; D010518:Periodontitis / Q000201:enzymology; D014086:Tooth Mobility / Q000517:prevention & control
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D015921:Dental Implants; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D004002:Clodronic Acid; D006051:Aurothioglucose; D017364:Collagenases; D020784:Matrix Metalloproteinase 8; D004318:Doxycycline; D002118:Calcium