ODAM mediates junctional epithelium attachment to tooth and tumorigenesis

Abstract

The odontogenic ameloblast-associated protein (ODAM) is known to play important roles in ameloblast differentiation, enamel mineralization, periodontal regeneration, and tumorigenesis. However, the underlying mechanism of ODAM function in various tissues remains largely unknown. The expression pattern and subcellular localization of ODAM was highly variable and dependent on cell types and their differentiation states, and that functional correlations exist in tooth and various cancer cells. During amelogenesis, Odam was localized in the nucleus, cytoplasm, and extracellular matrix (ECM) of ameloblasts. Runt-related transcription factor 2 (Runx2) regulated the expression of Odam and nuclear Odam served an important regulatory function in the mineralization of enamel through the regulation of matrix metalloproteinase-20 (MMP-20). ODAM was expressed in normal junctional epithelium (JE) of healthy tooth but was absent in pathologic pocket epithelium of diseased periodontium. In periodontitis and peri-implantitis, ODAM was extruded from JE following onset with JE attachment loss and detected in gingival crevicular fluid. Odam-mediated RhoA signaling resulted in actin filament rearrangement by interacting with Rho guanine nucleotide exchange factor 5 (Arhgef5). These results suggest that ODAM expression in JE reflects healthy periodontium, and that JE adhesion to the tooth surface is regulated via fibronectin/laminin-integrin-Odam-Arhgef5-RhoA signaling. Furthermore, ODAM has roles in inducing cancer cell adhesion, in part through binding, a positive regulator of Rho GTPases. ODAM-mediated RhoA signaling resulted in actin filament rearrangement by activating phosphatase and tensin homolog (PTEN) and inhibiting the phosphorylation of AKT. ODAM overexpression decreased motility, increased adhesion, and inhibited the metastasis of breast cancer cell line MCF7 cells. These results suggest that ODAM regulates MMP-20 in the nucleus, ODAM mediated cell adhesion by activating RhoA signaling in the cytoplasm, and the cytoplasmic ODAM was released in ECM after inflammation.