Cadherin 19 deficiency inhibits osteogenic differentiation and bone formation by regulating PI3K/AKT signaling pathway

BACKGROUND: Osteoporosis (OP) is a systemic bone disease characterized by damage to bone strength, leading to increased bone fragility and fracture risk. Cadherin 19 (CDH19) is located on chromosomes 18q22-q23, and 18q deletion is associated with terminal deletion diseases, including foot/hand deformities. However, the role of CDH19 in bone remains undefined. METHODS: A conditional knockout mouse model of the CDH19 gene was constructed using the Cre-loxP system, and the bone mass and bone morphology in mice were investigated using microCT and histological staining. Osteoblasts were isolated and cultured from wild-type and CDH19 knockout mice. Cell proliferation and differentiation were explored through EdU labeling, qPCR, alkaline phosphatase (ALP)/ alizarin red S (ARS) staining, and Western blot assays. The expression of genes altered in CDH19 gene knockout osteoblast was checked by RNA sequencing (RNA-seq), and subsequently confirmed by immunofluorescence and Western blot. RESULTS: We found that CDH19 could maintain the normal proliferation and differentiation in osteoblasts. After knocking out the CDH19 gene, the abilities of proliferation and osteogenesis were significantly inhibited in osteoblasts. Moreover, the bone mass of CDH19 knockout mice was significantly reduced, characterized by decreases in bone density, trabecular number, and bone volume fraction. The RNAseq analysis and western blot showed the PI3K/AKT signaling pathway was significantly inhibited in osteoblasts with CDH19 deletion. Furthermore, we demonstrated that administration of PI3K/AKT signaling pathway agonist 740Y-P partially alleviated the inhibition of osteogenic differentiation caused by CDH19 deletion in vitro and in vivo. CONCLUSION: This study demonstrated that CDH19 regulated osteogenic differentiation by modulating the PI3K/AKT signaling pathway in osteoblasts. CDH19 may become a novel target for the treatment of bone diseases.