Dept of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA.
Dept of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA; Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Life Sci. 2024 May 1;344:122583. doi: 10.1016/j.lfs.2024.122583. Epub 2024 Mar 19.
Formyl peptide receptor 1 (FPR1), from a G-protein coupled receptor family, was previously well-characterized in immune cells. But the function of FPR1 in osteogenesis and fracture healing was rarely reported. This study, using the FPR1 knockout (KO) mouse, is one of the first studies that try to investigate FPR1 function to osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in vitro and bone fracture healing in vivo.
Primary BMSCs were isolated from both FPR1 KO and wild type (WT) mice. Cloned mouse BMSCs (D1 cells) were used to examine role of FoxO1 in FPR1 regulation of osteogenesis. A closed, transverse fracture at the femoral midshaft was created to compare bone healing between KO and WT mice. Biomechanical and structural properties of femur were compared between healthy WT and KO mice.
FPR1 expression increased significantly during osteogenesis of both primary and cloned BMSCs. Compared to BMSCs from FPR1 KO mice, WT BMSCs displayed considerably higher levels of osteogenic markers as well as mineralization. Osteogenesis by D1 cells was inhibited by either an FPR1 antagonist cFLFLF or a specific inhibitor of FoxO1, AS1842856. In addition, the femur from WT mice had better biomechanical properties than FPR1 KO mice. Furthermore, bone healing in WT mice was remarkably improved compared to FPR1 KO mice analyzed by X-ray and micro-CT.
These findings indicated that FPR1 played a vital role in osteogenic differentiation and regenerative capacity of fractured bone, probably through the activation of FoxO1 related signaling pathways.
趋化因子受体 1（FPR1）属于 G 蛋白偶联受体家族，先前在免疫细胞中得到了很好的研究。但是，FPR1 在成骨和骨折愈合中的作用很少有报道。本研究使用 FPR1 敲除（KO）小鼠，是首次尝试研究 FPR1 功能的研究之一，旨在研究 FPR1 对骨髓来源干细胞（BMSCs）体外成骨分化和体内骨骨折愈合的影响。
从 FPR1 KO 和野生型（WT）小鼠中分离出原代 BMSCs。使用克隆的小鼠 BMSCs（D1 细胞）来研究 FoxO1 在 FPR1 调节成骨作用中的作用。在股骨中段造成闭合性横断骨折，以比较 KO 和 WT 小鼠之间的骨愈合情况。比较健康 WT 和 KO 小鼠的股骨生物力学和结构特性。
FPR1 在原代和克隆 BMSCs 的成骨过程中表达显著增加。与来自 FPR1 KO 小鼠的 BMSCs 相比，WT BMSCs 表现出更高水平的成骨标志物和矿化。D1 细胞的成骨作用受到 FPR1 拮抗剂 cFLFLF 或 FoxO1 的特异性抑制剂 AS1842856 的抑制。此外，WT 小鼠的股骨具有比 FPR1 KO 小鼠更好的生物力学特性。此外，通过 X 射线和 micro-CT 分析，WT 小鼠的骨折愈合明显优于 FPR1 KO 小鼠。
这些发现表明，FPR1 在成骨分化和骨折骨的再生能力中发挥了重要作用，可能是通过激活 FoxO1 相关信号通路。
