Faculdade de Medicina Dentária, Universidade do Porto, Portugal.
Bone. 2012 Jul;51(1):17-27. doi: 10.1016/j.bone.2012.03.015. Epub 2012 Mar 23.
Fluoroquinolones (FQs) are a class of antibiotics with a broad spectrum of activity, known to disturb bone metabolism. The aim of this work was to characterize the cellular and molecular effects of five FQs (ofloxacin, norfloxacin, ciprofloxacin, levofloxacin and moxifloxacin) in unstimulated and stimulated human osteoclast precursors. Peripheral blood mononuclear cells (PBMC) were cultured in the absence (unstimulated) or in the presence of osteoclastogenic factors (M-CSF and RANKL, stimulated), and were treated with FQs (0.3×10(-9)-10(-3) M), for 21 days. In unstimulated PBMC cultures, FQs (excepting moxifloxacin) exhibited a high osteoclastogenic potential, as shown by a significant increase in the expression of osteoclastic genes, TRAP activity and, specially, number of TRAP-positive multinucleated cells and calcium phosphate resorbing ability, suggesting the presence of mature and functional osteoclasts. Norfloxacin and levofloxacin induced the higher effect, followed by ciprofloxacin and ofloxacin. A decrease on apoptosis and an increase on M-CSF expression might have a possible contribution in the observed cellular behavior. In stimulated PBMC cultures, FQs further increase the osteoclastogenic response induced by M-CSF and RANKL (except ofloxacin). However, the osteoclastogenic response was much lower than that observed in unstimulated PBMC cultures. Both in unstimulated and stimulated PBMC cultures, for most of the FQs, the osteoclastogenic effects were observed in a wide range of concentrations, representative of plasmatic and tissue levels attained in several clinical settings. The various FQs differed on the stimulatory concentration range, the extent of the induced osteoclastogenic response and, also, on the dose- and time-dependent profile. Nevertheless, at high concentrations all the FQs seemed to elicit an increase on apoptosis. Additionally, some differences were noted in the intracellular signaling pathways tested, namely NFkB, MEK and PGE2 production. Results suggest that, considering the inter-individual variability of the FQs pharmacokinetics, the detailed biological profile of each FQ on bone cells is of utmost importance to clarify the effects of these compounds on bone metabolism.
氟喹诺酮类（FQs）是一类具有广谱活性的抗生素，已知会干扰骨代谢。本工作的目的是研究五种 FQs（氧氟沙星、诺氟沙星、环丙沙星、左氧氟沙星和莫西沙星）在未刺激和刺激人破骨细胞前体中的细胞和分子作用。外周血单核细胞（PBMC）在无刺激（未刺激）或存在破骨细胞生成因子（M-CSF 和 RANKL，刺激）的情况下培养，并以 0.3×10（-9）-10（-3）M 的浓度用 FQs 处理 21 天。在未刺激的 PBMC 培养物中，除莫西沙星外，FQs 表现出高的破骨细胞生成潜力，这表现为破骨细胞基因的表达、TRAP 活性显著增加，特别是 TRAP 阳性多核细胞的数量和钙磷吸收能力增加，表明存在成熟和功能齐全的破骨细胞。诺氟沙星和左氧氟沙星诱导的效果最高，其次是环丙沙星和氧氟沙星。细胞凋亡的减少和 M-CSF 表达的增加可能对观察到的细胞行为有一定的贡献。在刺激的 PBMC 培养物中，FQs 进一步增加了 M-CSF 和 RANKL 诱导的破骨细胞生成反应（除氧氟沙星外）。然而，破骨细胞生成反应远低于未刺激的 PBMC 培养物。在未刺激和刺激的 PBMC 培养物中，大多数 FQs 在广泛的浓度范围内表现出破骨细胞生成作用，代表了在多种临床情况下达到的血浆和组织水平。各种 FQs 在刺激浓度范围、诱导的破骨细胞生成反应的程度以及剂量和时间依赖性特征上存在差异。然而，在高浓度下，所有 FQs 似乎都能引起细胞凋亡增加。此外，在测试的细胞内信号通路中也观察到一些差异，即 NFkB、MEK 和 PGE2 的产生。结果表明，考虑到 FQs 药代动力学的个体间变异性，每种 FQ 对骨细胞的详细生物学特征对于阐明这些化合物对骨代谢的影响至关重要。
