Effects of unfractionated heparin and rivaroxaban on the expression of heparanase and fibroblast growth factor 2 in human osteoblasts

Abstract

Long-term treatment with anticoagulants may contribute to osteoporosis. Although unfractionated heparin and rivaroxaban have adverse effects on bone microstructure and function in adult rats, the underlying mechanism remains to be elucidated. Heparanase (HPSE) and fibroblast growth factor (FGF)2 are important signals in bone formation and fracture healing. Therefore, the present study was designed to investigate the effects of unfractionated heparin and rivaroxaban on the expression of HPSE and FGF2 in human osteoblasts. Human osteoblasts were treated with unfraction-ated heparin (0.5-50 IU/ml) or rivaroxaban (0.13-13 μg/ml) for different durations. Plasmids encoding HPSE and FGF2 were transfected into osteoblasts, and cell viability was assessed using MTT assays, with mRNA and protein expression levels determined using reverse transcription-quantitative poly-merase chain reaction and western blot analyses, respectively. Osteoblast growth was significantly inhibited by treatment with unfractionated heparin (50 IU/ml) or rivaroxaban (13 μg/ml). Unfractionated heparin alone significantly inhibited the expression of HPSE and FGF2, whereas rivaroxaban inhibited the expression of FGF2 without affecting that of HPSE. Furthermore, the overexpression of HPSE or FGF2 significantly reversed the inhibitory effects of unfraction-ated heparin and rivaroxaban on osteoblasts. These findings suggested that HPSE and FGF2 signals were involved in the detrimental role of unfractionated heparin and rivaroxaban in human osteoblasts, providing novel information on the side effects of anticoagulants.