FasL in osteogenesis, periodontal health and disease

Content of research project: FasL controls development, remodeling and regeneration of the axial and the appendicular skeleton in health and disease, however the role of FasL to maintain periodontal health has not been discovered so far. Recently, sclerostin (Sost) expression was fond to be decreased in the mandibular bone of FasL deficient mice by the Czech team thereby suggesting a non-apoptotic function of FasL. Hypotheses: The overall goal of this project is twofold: First, there is an interaction between FasL and other key molecules such as Sost with respect to odontogenesis and osteogenesis. Second, FasL is involved in periodontal health and disease. Methods: To test the first hypothesis the following three strategies are proposed: (i) To confirm Sost expression modulation by FasL, (ii) to challenge possible reciprocal interactions between FasL and Sost, (iii) to decipher the molecular mechanism(s) behind FasL and Sost interactions. To achieve the aims, in vivo PCR array analysis, in vitro modulatory experiments and whole genome microarrays will be applied. FasL deficient mice and cells related to osteogenesis and odontogenesis, particularly osteocytes, odontoblasts and cementoblasts will be examined. To test the second hypothesis, three approaches are suggested: (i) To describe the dental and periodontal phenotype of FasL knockout mice. (ii) To study healing of extraction sockets of the first incisor in FasL knockout mice. (iii) To investigate the role of FasL in regulation lipopolysaccharide (LPS)-induced periodontitis in mice. An explanation indicating what is new about the project: The project is original because the non- apoptotic function of FasL are not extensively investigated and open new insights into the biology of FasL being a key trigger of apoptosis. The project is also original because we aim to discover the role of FasL in tooth and periodontal development, healing of extraction sockets and also periodontal inflammation and tissue destruction.

Fas ligand (FasL) belongs to the tumor necrosis factor (TNF) superfamily regulating bone turnover. We performed a phenotypical analysis of mice carrying the homozygous Fasl mutation and wild-type (WT) mice under healthy conditions and upon ligature-induced periodontitis. We also studied the impact of FasL on osseous healing in extraction sockets. Based on sophisticated CT and histological analyses we can report that healthy Fasl mice have more periodontal bone than WT littermates. Fasl had no significant effect on inflammatory osteolysis compared to WT controls with ligatures. Moreover, FasL deficiency reduced bone regeneration during the healing process of extraction sockets. These findings suggest that FasL is a catabolic factor in alveolar bone homeostasis, however, FasL does not affect the inflammatory osteolysis, and even stimulates the healing of extraction sockets.