Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Anam Hospital, 126-1 Anamdong 5-ga, Seoul, Korea.
Int J Mol Med. 2010 Dec;26(6):877-83. doi: 10.3892/ijmm_00000537.
The use of proton pump inhibitors (PPIs) seems to be related to increased fracture risk but the mechanism is unclear. In an effort to clarify the mechanism, we evaluated the effect of omeprazole, a representative of the PPIs, on the expression of transcription factors in osteoclasts and osteoblasts. Murine RAW264.7 and MC3T3-E1 cells were used for osteoclast and osteoblast analysis, to which various concentrations of omeprazole were added. RAW264.7 cells with ≥3 nuclei were considered tartrate-resistant acid phosphatase (TRAP)-positive, i.e. activated osteoclasts. Expressions of the calcitonin receptor (CTR), c-fos, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), and matrix metalloproteinase (MMP)-9 mRNA in osteoclasts were evaluated. Gene expression of osteocalcin and of the osteoprotegerin/receptor activator of NF-κB ligand (OPG/RANKL) ratio in osteoblasts was examined and Western blotting of NFATc1 was performed. Treating the osteoclasts with increasing doses of omeprazole did not affect TRAP positivity, but significantly decreased the expressions of CTR, c-fos, NFATc1, and MMP-9 regardless of the omeprazole concentration. The expression of osteocalcin and of the OPG/RANKL ratio in osteoblasts was augmented with increasing omeprazole concentrations. The result of the Western blot analysis with NFATc1 was similar to that of the expression of NFATc1 mRNA. Omeprazole decreased the activation of osteoclasts but increased that of osteoblasts in vitro, in part causing an osteopetrosis-like effect. Together with the effect of omeprazole on calcium homeostasis, increased fracture risk may be due to the osteopetrorickets-like effect of omeprazole.
质子泵抑制剂（PPIs）的使用似乎与骨折风险增加有关，但机制尚不清楚。为了阐明这一机制，我们评估了奥美拉唑（一种 PPI 的代表）对破骨细胞和成骨细胞中转录因子表达的影响。使用鼠 RAW264.7 和 MC3T3-E1 细胞进行破骨细胞和成骨细胞分析，并向其中加入不同浓度的奥美拉唑。具有≥3 个核的 RAW264.7 细胞被认为是抗酒石酸酸性磷酸酶（TRAP）阳性，即激活的破骨细胞。评估破骨细胞中降钙素受体（CTR）、c-fos、激活 T 细胞的核因子 1（NFATc1）和基质金属蛋白酶（MMP）-9 mRNA 的表达。检查成骨细胞中骨钙素和成骨保护素/核因子-κB 配体受体激活剂（OPG/RANKL）的比值的基因表达，并进行 NFATc1 的 Western 印迹分析。用递增剂量的奥美拉唑处理破骨细胞不会影响 TRAP 阳性，但无论奥美拉唑浓度如何，均显著降低 CTR、c-fos、NFATc1 和 MMP-9 的表达。随着奥美拉唑浓度的增加，成骨细胞中骨钙素和成骨保护素/核因子-κB 配体受体激活剂（OPG/RANKL）的比值表达增加。NFATc1 的 Western 印迹分析结果与 NFATc1 mRNA 的表达相似。奥美拉唑在体外降低破骨细胞的激活，但增加成骨细胞的激活，部分导致类骨质减少症样效应。结合奥美拉唑对钙稳态的影响，骨折风险的增加可能是由于奥美拉唑的类骨质减少症样作用。
