Local simvastatin effects on mandibular bone growth and inflammation
Local simvastatin effects on mandibular bone growth and inflammation
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DOI：
10.1902/jop.2005.76.11.1861
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发表时间：
2005-11-01
影响因子：
4.3
通讯作者：
Reinhardt, RA
中科院分区：
文献类型：
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作者：
Stein, D;Lee, YJ;Reinhardt, RA
背景：辛伐他汀已被证明局部应用于小鼠骨骼时可促进骨生长；然而，高剂量（2.2毫克）会引起相当大的软组织炎症，使未来的临床使用成为问题。本研究评估了低剂量辛伐他汀和环氧化酶（COX）合成酶抑制剂对大鼠组织炎症和骨生长以及小鼠基因表达的影响。方法：成年雌性大鼠未经治疗或在下颌骨侧面用聚乳酸膜（SIM）甲基纤维素凝胶（0.1、0.5、1.0、1.5或2.2 mg）单剂量处理辛伐他汀。对侧下颌骨侧单独植入甲基纤维素凝胶/聚乳酸膜（gel），每组5只大鼠分别于3、7、24天后进行组织形态学评价。随后的大鼠同样给予0.5 mg辛伐他汀（最佳剂量）和每日腹腔注射COX-2抑制剂（NS-398, 1 mg/kg × 7天，N = 16）、普通COX抑制剂（吲哚美辛，1 mg/kg × 7天，N = 16）或无抑制剂（N = 10），并在7天或24天后通过方差分析（ANOVA）评估组织形态学。基因阵列还用于评估0.5 mg辛伐他汀在小鼠颅骨（N = 12）中的成骨基因表达。结果：与凝胶对照组相比，0.5 mg辛伐他汀组骨面积增加45% （P < 0.001，与2.2 mg剂量组相似），临床肿胀与高剂量辛伐他汀组相比减少（P < 0.05）。0.1 mg辛伐他汀剂量未能显著刺激骨生长。NS-398和吲哚美辛可以减少炎症和骨骼生长。辛伐他汀显著上调前胶原蛋白、纤维连接蛋白和基质金属蛋白酶-13基因。结论：将辛伐他汀的剂量从2.2 mg减少到0.5 mg，在不牺牲骨生长潜力的情况下，将炎症降低到临床更可接受的水平，但cox相关的炎症似乎是体内骨生长所必需的。
Background: Simvastatin has been shown to increase bone growth when applied topically to murine bone; however, it causes considerable soft tissue inflammation at high doses (2.2 mg), making future clinical use problematic. This study evaluated the effect of lower simvastatin doses and cyclooxygenase (COX) synthase inhibitors on tissue inflammation and bone growth in rats and gene expression in mice.Methods: Adult female rats were untreated or treated with a single dose of 0.1, 0.5, 1.0, 1.5, or 2.2 mg simvastatin in methylcellulose gel in a polylactic acid membrane (SIM) on the lateral aspect of the mandible. The contralateral mandible side was implanted with methylcellulose gel/polylactic acid membrane alone (GEL), and five rats in each dose pairing were evaluated histomorphometrically after 3, 7, and 24 days. Subsequent rats were similarly treated with 0.5 mg simvastatin (optimal dose) and daily intraperitoneal injections of COX-2 inhibitor (NS-398; 1 mg/kg x 7 days; N = 16), general COX inhibitor (indomethacin; 1 mg/kg x 7 days; N = 16), or no inhibitor (N = 10) and evaluated histomorphometrically after 7 or 24 days by analysis of variance (ANOVA). Gene arrays were also used to evaluate osteogenic gene expression from 0.5 mg simvastatin in murine calvaria (N = 12).Results: There was a 45% increase in bone area with 0.5 mg simvastatin versus gel control (P < 0.001; similar to the 2.2-mg dose), and clinical swelling was reduced compared to the high simvastatin dose (P < 0.05). The 0.1-mg simvastatin dose failed to stimulate significant bone growth. NS-398 and indomethacin reduced inflammation and bone growth. Simvastatin significantly upregulated procollagen, fibronectin, and matrix metalloproteinase-13 genes.Conclusion: Reducing the simvastatin dose from 2.2 to 0.5 mg reduced inflammation to a more clinically acceptable level without sacrificing bone-growth potential, but COX-associated inflammation appears to be necessary for in vivo bone growth.