LP533401 treatment alters vitamin K metabolism, bone Gla-OC/Glu-OC ratios, and improves mineral status of the skeleton in rats with chronic kidney disease.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is associated with impaired bone mineralization and vitamin K (VK) deficiency. Peripheral serotonin (5-HT) adversely affects bone integrity, but its relationship with VK metabolism remains unknown. In this study, we investigated the effects of LP533401 (LP), a small molecule inhibitor of peripheral 5-HT synthesis in the gut, on VK metabolism, VK-dependent proteins (VKDPs), and mineral status of the skeleton in CKD rats. METHODS: Serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), serum and bone VKDPs concentrations, bone VK cycle genes expression, and mineral status of the skeleton were determined in CKD rats treated with vehicle or LP at the dose of 30 or 100 mg/kg daily. RESULTS: LP treatment altered VK metabolism by restoring circulating VK1 levels and promoting MK7 over MK4 synthesis. At the molecular level, LP treatment modulated the expression of VK cycle genes (UBIAD1, VKORC1, GGCX) and improved bone γ-carboxylation efficiency, particularly in trabecular bone. LP at 30 mg/kg most effectively enhanced bone mineral parameters of the skeleton, while the 100 mg/kg dose had site-specific effects, restoring mainly cortical bone mineralization. Correlations between MK7 and bone densitometric parameters highlight its functional role in restoring mineral homeostasis. CONCLUSION: LP treatment modulates VK metabolism, VKDPs levels in bone and serum, and improves bone mineralization in the rat CKD model. This study provides a new perspective on the therapeutic potential targeting the modulation of peripheral serotonin and VK-dependent signaling to improve bone mineralization, which is impaired in CKD-MBD.