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Amelogenesis consists of secretory, transition, maturation, and post-maturation stages, and the morphological changes of ameloblasts at each stage are closely related to their function. p130 Crk-associated substrate (Cas) is a scaffold protein that modulates essential cellular processes, including cell adhesion, cytoskeletal changes, and polarization. The expression of p130Cas was observed from the secretory stage to the maturation stage in ameloblasts. Epithelial cell-specific p130Cas-deficient (p130CasΔepi-) mice exhibited enamel hypomineralization with chalk-like white mandibular incisors in young mice and attrition in aged mouse molars. A micro-computed tomography analysis and Vickers micro-hardness testing showed thinner enamel, lower enamel mineral density and hardness in p130CasΔepi- mice in comparison to p130Casflox/flox mice. Scanning electron microscopy, and an energy dispersive X-ray spectroscopy analysis indicated the disturbance of the enamel rod structure and lower Ca and P contents in p130CasΔepi- mice, respectively. The disorganized arrangement of ameloblasts, especially in the maturation stage, was observed in p130CasΔepi- mice. Furthermore, expression levels of enamel matrix proteins, such as amelogenin and ameloblastin in the secretory stage, and functional markers, such as alkaline phosphatase and iron accumulation, and Na+/Ca2++K+-exchanger in the maturation stage were reduced in p130CasΔepi- mice. These findings suggest that p130Cas plays important roles in amelogenesis (197 words).

Endochondral ossification is important for skeletal development. Recent findings indicate that the p65 (RelA) subunit, a main subunit of the classical nuclear factor-κB (NF-κB) pathway, plays essential roles in chondrocyte differentiation. Although several groups have reported that the alternative NF-κB pathway also regulates bone homeostasis, the role of the alternative NF-κB pathway in chondrocyte development is still unclear. Here, we analyzed the in vivo function of the alternative pathway on endochondral ossification using p100-deficient (p100−/−) mice, which carry a homozygous deletion of the COOH-terminal ankyrin repeats of p100 but still express functional p52 protein. The alternative pathway was activated during the periarticular stage in wild-type mice. p100−/− mice exhibited dwarfism, and histological analysis of the growth plate revealed abnormal arrangement of chondrocyte columns and a narrowed hypertrophic zone. Consistent with these observations, the expression of hypertrophic chondrocyte markers, type X collagen (ColX) or matrix metalloproteinase 13, but not early chondrogenic markers, such as Col II or aggrecan, was suppressed in p100−/− mice. An in vivo BrdU tracing assay clearly demonstrated less proliferative activity in chondrocytes in p100−/− mice. These defects were partly rescued when the RelB gene was deleted in p100−/− mice. Taken together, the alternative NF-κB pathway may regulate chondrocyte proliferation and differentiation to maintain endochondral ossification.