IL-1 and TNF activity partially account for calvarial bone resorption induced by local injection of LPS
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Abstract
Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, triggers monocytes and other host cells to synthesize proinflammatory mediators, including IL-1 and TNF. Despite extensive research, both in vivo and in vitro, the exact mechanisms by which LPS stimulates bone resorption are not fully understood. The present study was undertaken to test the hypothesis that TNF and/or IL-1 activity mediate LPS-induced bone resorption in vivo. LPS has been implicated in the initiation and development of periodontal disease. IL-IR(-/-), TNF p55(-/-)/p75(-/-), and TNF p55(-/-)/IL-1R(-/-), ICE mice and their respective wild-type mice were given a local calvarial injection of P. gingivalis LPS and sacrificed after 5 days. In a time course experiment with E. coli LPS, it was determined that active resorption peaks 5 days after endotoxin stimulation in the wild-type control groups. The osteoclast response was compared histologically between the groups. Three different concentrations of P. gingivalis LPS were used: 500 µg, 100 µg and 20 µg diluted in 100 µl of 0.9% saline solution. Sections were stained for tartrate-resistant acid phosphatase (TRAP), and histomorphometric analysis was performed to quantify osteoclast number and area. At the highest dose (500 µg), a significant decrease in the number of osteoclasts occurred in the mutant mice compared with wild-type mice-a 41% reduction in TNF p55(-/-)/p75(-/-) mice, a 57% reduction in IL-1R(-/-) mice, a 64% reduction in mice that lacked both IL-1 and TNF receptors (TNF p55(-/-)/1L- 1R (-/-), and a 38% reduction in ICE (-/-) mice. At lower doses (100 µg and 20 µg), there was no significant difference in bone resorption between the knockout and wild-type animals. From these results, we concluded that at high doses, LPS-induced bone resorption is mediated in part by IL-1 and TNF receptors. However, IL-1 receptor signaling appears to be more important than TNF. Results in the ICE(-/-) mice suggest that IL-1(beta) is a potent in vivo bone-resorbing cytokine. The decrease in bone resorption observed in knockout animals is associated with a reduction in osteoclast number and surface, but not activity per osteoclast. At lower doses, LPS-stimulated osteoclastogenesis appears to be independent of IL- 1 and TNF activity.
Description
Thesis (MSD)--Boston University, Henry M. Goldman School of Dental Medicine, 1998 (Periodontology and Oral Biology)
Includes bibliographic references: leaves 48-60.
Includes bibliographic references: leaves 48-60.
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