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The periodontal junctional epithelium (JE) is maintained in a steady state through a dynamic process that balances proliferation and exfoliation of epithelial cells. However, mechanisms that regulate JE are not well understood. To better understand how proliferation of the JE is controlled in healthy gingiva, we have studied functional roles of the CDK (cyclin dependent kinase) inhibitors p21 and p27 in JE using knockout mouse model systems. Image analysis of the dentogingival junction in p21 or p27 single knockout mice as well as p21/p27 double knockout mice (dKO) was performed. The analysis revealed enlarged JE in p21/p27 dKO mice due to an increase in the area of the epithelium and associated connective tissue ‘islands’. Immunohistochemistry was performed for p21, p27, cyclin D1, and proliferating cell nuclear antigen (PCNA). The highest levels of PCNA-positive cells were detected in the p21/p27 dKO mice, reflecting increased cell turnover. Lower levels of cyclin D1 were detected in the JE of p21/p27 knockout mice, suggesting that p21 and p27 regulate stability of cyclin D1 in oral epithelium. These data suggest that p21 and p27 have a critical role in controlling epithelial cell proliferation in the JE and thus function to maintain the JE at a normal size.