Experimental arthritis in rats induces biomarkers of periodontitis which are ameliorated by gene therapy with tissue inhibitor of matrix metalloproteinases.
BACKGROUND
Periodontal disease (PD) and rheumatoid arthritis (RA) share many common pathophysiologic features, but a clinical relationship between the two conditions remains controversial, in part because of the confounding effects of anti-inflammatory drug therapy universally used in the latter disease. To further explore this issue, inflammatory arthritis was induced in rats to determine the effect on gingival biomarkers of inflammation and tissue destruction and to investigate the effect of a therapeutic intervention devoid of conventional anti-inflammatory properties.


METHODS
Adjuvant arthritis (AA) was induced in Lewis male rats by injecting mycobacterium cell wall in complete Freund's adjuvant using standard techniques. One group of animals was treated by induction of systemic tissue inhibitor of matrix metalloproteinases (TIMP-4). At 3 weeks, arthritis severity was recorded and both paw and gingival tissues were collected for matrix metalloproteinase activity (MMP) and cytokine analysis. In addition, the maxillary jaws were removed for assessment of periodontal bone loss.


RESULTS
The development of arthritis was associated with elevated joint tissue MMPs, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta levels compared to control rats. In the gingival tissue of the untreated arthritic rats, gelatinase, collagenase, TNF-alpha, and IL-1beta were also elevated compared to control rats. Periodontal bone loss and tooth mobility were also increased significantly (P <0.05) in untreated arthritic rats. All parameters improved after TIMP-4 gene therapy.


CONCLUSIONS
To our knowledge, this is the first study to report an association between experimental systemic arthritis in rats and elevated gingival tissue MMPs, cytokine levels, and periodontal disease. Reversal of these changes with TIMP-4 gene therapy strengthens the pathophysiologic correlation between systemic and local disease.
Department of Oral Biology and Pathology, School of Dental Medicine, State University of New York at Stony Brook, NY 11794, USA. nramurthy@notes.cc.sunysb.edu
Nungavaram S
NS
Ramamurthy
Robert A
RA
Greenwald
Mohamed Y
MY
Celiker
Eric Y
EY
Shi
D016301:Alveolar Bone Loss / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D005528:Foot; D015316:Genetic Therapy; D005881:Gingiva / Q000201:enzymology; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010518:Periodontitis / Q000378:metabolism*; D010957:Plasmids; D011480:Protease Inhibitors / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D014086:Tooth Mobility / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
D015415:Biomarkers; D007375:Interleukin-1; D020782:Matrix Metalloproteinases; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D000097792:Tissue Inhibitor of Metalloproteinase-4