Background: The LPS of A.actinomycetemcomitans is one of the major pathogenic factors in periodontal disease. It induces secretion of pro-inflammatory cytokines and involves in alveolar bone destruction. We hypothesized that the LPS of A.actinomycetemcomitans could affect the activation of MMP-2 and the expression of RANKL and OPG in HPDL cells leading to the destruction of periodontium. Methods: HPDL cells were cultured in serum-free medium with or without the LPS of A.actinomycetemcomitans for 36 hours. The activation of MMP-2 was analyzed by zymography. Changes of the expression of RANKL and OPG were examined by reverse transcription-polymerase chain reaction and supported by western blot analysis. Results: The activation of MMP-2 could be induced by the LPS of A.actinomycetemcomitans in HPDL cells and could be inhibited by a serine protease inhibitor. The result suggested that the LPS might activate MMP-2 through a serine protease-dependent pathway. The activation was also blocked by NF-kB inhibitor, which indicated the involvement of NF-kB. The up-regulation of RANKL but not OPG by the LPS was found in both transcription and translation and could be abolished by Indomethacin. In addition, serine protease inhibitor also inhibited the up-regulation of RANKL, suggesting the activity of serine protease.