Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon Dong, Geumjeong gu, Busan 609-735, Korea.
J Biol Chem. 2011 May 13;286(19):17133-43. doi: 10.1074/jbc.M110.197772. Epub 2011 Mar 3.
Binding of N-formyl-methionyl-leucyl-phenylalanine (fMLP) to its specific cell surface receptor, N-formyl peptide receptor (FPR), triggers different cascades of biochemical events, eventually leading to cellular activation. However, the physiological role of fMLP and FPR during differentiation of mesenchymal stem cells is unknown. In this study, we attempted to determine whether fMLP regulates differentiation of mesenchymal stem cells derived from bone marrow. Analysis by quantitative-PCR and flow cytometry showed significantly increased expression of FPR1, but not FPR2 and FPR3, during osteoblastic differentiation. fMLP, a specific ligand of FPR1, promotes osteoblastic commitment and suppresses adipogenic commitment under differentiation conditions. Remarkably, fMLP-stimulated osteogenesis is associated with increased expression of osteogenic markers and mineralization, which were blocked by cyclosporine H, a selective FPR1 antagonist. In addition, fMLP inhibited expression of peroxisome proliferator-activated receptor-γ1, a major regulator of adipocytic differentiation. fMLP-stimulated osteogenic differentiation was mediated via FPR1-phospholipase C/phospholipase D-Ca(2+)-calmodulin-dependent kinase II-ERK-CREB signaling pathways. Finally, fMLP promoted bone formation in zebrafish and rabbits, suggesting its physiological relevance in vivo. Collectively, our findings provide novel insight into the functional role of fMLP in bone biology, with important implications for its potential use as a therapeutic agent for treatment of bone-related disorders.
N-甲酰基-甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）与它的特定细胞表面受体 N-甲酰肽受体（FPR）结合，引发不同的生化事件级联反应，最终导致细胞激活。然而，fMLP 和 FPR 在间充质干细胞分化过程中的生理作用尚不清楚。在这项研究中，我们试图确定 fMLP 是否调节骨髓来源的间充质干细胞的分化。定量 PCR 和流式细胞术分析显示，在成骨分化过程中，FPR1 的表达显著增加，而 FPR2 和 FPR3 则没有增加。fMLP 是 FPR1 的特异性配体，在分化条件下促进成骨细胞的定向分化，并抑制脂肪细胞的定向分化。值得注意的是，fMLP 刺激的成骨作用与成骨标志物的表达增加和矿化有关，而这些作用被 FPR1 选择性拮抗剂环孢菌素 H 阻断。此外，fMLP 抑制了过氧化物酶体增殖物激活受体-γ1 的表达，而过氧化物酶体增殖物激活受体-γ1 是脂肪细胞分化的主要调节因子。fMLP 通过 FPR1-磷脂酶 C/磷脂酶 D-Ca(2+)-钙调蛋白依赖性激酶 II-ERK-CREB 信号通路刺激成骨细胞分化。最后，fMLP 促进了斑马鱼和兔的骨形成，表明其在体内的生理相关性。总之，我们的研究结果为 fMLP 在骨生物学中的功能作用提供了新的见解，这对于将其作为治疗与骨相关疾病的治疗剂具有重要意义。
