Platelet factor 4 induces bone loss by inhibiting the integrin α5-FAK-ERK pathway

Abstract: Background The effect of platelet factor 4 (PF4) on bone marrow mesenchymal stem cells (BMMSCs) and osteoporosis remains poorly understood. Hence, this study aimed to evaluate the effects of PF4-triggered bone destruction of mice and determine the underlying mechanism. Methods Firstly, in vitro cell proliferation and cell cycle of BMMSCs were assessed by a CCK8 assay and flow cytometry, respectively. Osteogenic differentiation was confirmed using staining and quantification of alkaline phosphatase and alizarin red. Next, an osteoporotic mouse model was established by performing bilateral ovariectomy. Furthermore, the Pf4 concentrations were obtained using ELISA. The bone microarchitecture of the femur was evaluated by microCT and histological analyses. Finally, the key regulators on osteogenesis and pathways were investigated by qPCR and WB. Results Human PF4 widely and moderately lessened the cell proliferation and osteogenic differentiation ability of BMMSCs. Furthermore, the level of Pf4 in the serum and BM were generally increased, whereas the bone microarchitecture deteriorated due to OVX surgery. Moreover, in vivo mouse Pf4 supplementation triggered bone deterioration of the femur. Besides, several key regulators of osteogenesis were down-regulated and the integrin α5 (ITGA5)-FAK-ERK pathway was inhibited due to PF4 supplementation. Conclusions PF4 may be related to OVX-induced bone loss triggered by the suppression of bone formation in vivo and alleviated BMMSC osteogenic differentiation through inhibiting the ITGA5-FAK-ERK pathway.