The bisphosphonate zoledronic acid regulates key angiogenesis-related genes in primary human gingival fibroblasts.

BACKGROUND: Osteonecrosis of the jaws is recognised as a serious complication for patients receiving bisphosphonates. The anti-angiogenic effects of bisphosphonates have been implicated in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The purpose of this study was to determine the effects of zoledronic acid on cultured human gingival fibroblasts in relation to the modulation of genes associated with angiogenic regulation. METHODS: Primary cultures of fibroblasts were developed from gingival tissues excised during crown-lengthening surgery from three patients. Cells were cultured with and without 30µM zoledronic acid for 6, 12 and 24h and cellular proliferation and migration investigated using CellTiter-Blue and scratch wound assays, respectively. Gene expression was determined using semi-quantitative PCR array technology that allowed the analysis of 84 pathway-focused genes known to be important in the regulation of angiogenesis. RESULTS: Zoledronic acid increased the proliferation of the gingival fibroblasts in a dose dependent manner with 12 and 24h of exposure. Scratch wounding of the human gingival fibroblasts and treatment with increasing doses and time exposure to zoledronic acid (ZA) inhibited their migration. Statistically significant increases in gene expression were found for RHOB, VEGFA, CD55 and BMP2 (p≤0.05) in response to 30µM zoledronic acid. CCL2 and IL6 genes were significantly downregulated (p≤0.05). CONCLUSIONS: The regulation of the prenylated protein RHOB in this study was consistent with the known effects of zoledronic acid on the mevalonate pathway. The down regulation of CCL2 and IL6 and the upregulation of CD55 may be associated with suppression of inflammation. An increase in VEGFA and BMP2 gene expression suggests that fibroblasts respond to zoledronic acid by producing a proangiogenic environment.

The immunopathogenesis of periodontal disease.

Treatment planning in periodontics, as with any disease, must be based on an understanding of the aetiology and pathogenesis of the disease. In this context, it has slowly become recognized over the past three decades that while plaque is the cause of the disease, it is the innate susceptibility of the host that determines the ultimate outcome of the disease process. Innate susceptibility, in turn, is determined by the nature of the immune response to the specific periodontopathic complexes comprising the plaque biofilm. The aim of this review was to examine current understanding of the immunopathogenesis of chronic periodontitis with respect to its possible clinical implications in terms of treatment planning and risk assessment. Numerous studies have demonstrated that the periodontitis lesion itself involves predominantly B cells and plasma cells, while the gingivitis lesion is primarily a T cell mediated response. This led to the concept over 30 years ago that the development of periodontitis involves a switch from a T cell lesion to one involving large numbers of B cells and plasma cells. It is also well recognized that control of this shift is mediated by a balance between the so-called Th1 and Th2 subsets of T cells, with chronic periodontitis being mediated by Th2 cells. More recently, T regulatory (Treg) and Th17 cells have been demonstrated in periodontal tissues, raising the possibility that these cells are also important in the immunoregulation of periodontal disease. The clinical implications of these observations can be seen in the fact that identification of Th1/Th2 and Treg/Th17 cytokine gene expression in the peripheral blood and salivary transcriptomes is now being trialled as a possible marker of disease susceptibility. If this proves to be the case, a chairside salivary diagnostic could be developed within the next five to 10 years.