Defining the functional role of cytokines in tooth eruption
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Tooth eruption provides an excellent model to examine osseous metabolism as bone resorption (occlusal area), and formation (apical area), occur simultaneously and are spatially separated. Monocytes are thought to play an important role in regulation of bone metabolism. The goal of this study was to examine recruitment of monocytes to bone undergoing developmental remodeling in C57BL/6J mice. To account for potential mechanism for monocyte recruitment, we investigated expression of monocyte chemoattractant protein-1 (MCP-1) in tissues surrounding an erupting tooth. TNF and IL1 are potent stimulators of bone resorption. Recent evidence shows that these proinflammatory cytokines are expressed during embryogenesis and may participate in developmental tissue remodeling. To establish their role in tooth eruption and bone remodeling, we carried out experiments using mice with genetic deletions of TNFR1/IL-1R1 or TNFR1/TNFR2. Mandibles were obtained from animals sacrificed at various time points from birth to 14 days of age. Histological sections were stained using immuno/histochemistry to identify mononuclear phagocytes, osteoclasts, MCP-1-positive and apoptotic cells. The results demonstrated that a significant time-dependent increase in recruitment of monocytes in the occlusal area (bone resorption) at days 5 and 9 was associated with significant increase in number of osteoclasts at similar time points. In contrast, in the apical area (bone formation), a significant time-dependent increase in monocyte recruitment was coupled with a decrease in number of osteoclasts, found in high numbers at earliest time points (up to day 3 postnatally). The number of MCP-1 positive cells also increased with time in both areas and was generally proportional to the recruitment of mononuclear phagocytes. Osteoblasts were the principal bone cell type expressing MCP-1. Our results suggest that monocytes have different functional roles in areas of bone resorption and bone formation. Furthermore, the expression of MCP-1 is developmentally regulated and may provide mechanistic basis to explain the recruitment of monocytes. Functional deletion of TNFR1/IL-1R1 resulted in later onset of molar eruption. However, histological findings showed that only monocyte physiology in the occlusal connective tissue was affected by loss of TNFR1/IL-1R1 signaling. Increased number of monocytes in the area was observed during tooth eruption through subgingival connective tissue (day 13). Presence of monocytes in the dental follicle or presence of osteoclasts at the adjacent bone surface was not altered. Deletion of TNFR1/R2 affected recruitment/function/survival of monocytes and rate of apoptosis only in the apical area during intraosseous stage of tooth eruption (day 9). No changes in monocyte or osteoclast markers were noted in the occlusal area. Loss of TNFR1/R2 signaling had no effect on the rate of molar eruption. Lack of striking differences between the experimental and the wild type groups indicates that TNF and IL-1 do not play a critical role during tooth eruption and remodeling of surrounding bone, supporting the suggested hypothesis that tooth eruption is a redundantly regulated process.
Thesis (D.Sc.D.)--Boston University, Henry M. Goldman School of Dental Medicine, 1999.Includes bibliographical references (leaves 90-106).
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