Zhang Yun, Yan Ming, Yu Qing-Feng, Yang Pei-Fan, Zhang Hai-Dong, Sun Yong-Hong, Zhang Zhi-Fen, Gao Yun-Feng
College of Medicine, Shaoxing University.
Biol Pharm Bull. 2016;39(12):2028-2035. doi: 10.1248/bpb.b16-00522.
Osteolysis induced by chronic Gram-negative bacterial infection underlies many bone diseases such as osteomyelitis, septic arthritis, and periodontitis. Drugs that inhibit lipopolysaccharide (LPS)-induced osteolysis are critically needed for the prevention of bone destruction in infective bone diseases. In this study, we assessed the effect of puerarin, a natural isoflavone isolated from Pueraria lobata OHWI root, on LPS-induced osteoclastogenesis and bone loss. Our in vitro study showed that puerarin significantly inhibited LPS-induced osteoclast differentiation from osteoclast precursor RAW264.7 cells. The inhibition occurred through suppressing the production of osteoclast activating factor tumor necrosis factor (TNF)-α, interleukin (IL)-1β and prostaglandin E (PGE), which led to down-regulating mRNA expression of osteoclastogenic genes including tartrate-resistant acid phosphatase (TRAP), cathepsin K and matrix metalloprotein 9 (MMP-9). Furthermore, LPS triggered activation of Akt in osteoclast precursor RAW264.7 cells, which was inhibited by puerarin treatment. In vivo, puerarin attenuated LPS-induced bone loss in a murine calvarial osteolysis model. Collectively, puerarin prevents LPS-induced osteoclast formation, function and bone loss, where the inhibition of Akt activation plays an important role. These findings provide evidences that puerarin might be beneficial as a promising candidate drug for the prevention and treatment of bacteria-induced bone destruction disease, and give new insights for understanding its possible mechanism.
慢性革兰氏阴性细菌感染引起的骨溶解是许多骨疾病（如骨髓炎、化脓性关节炎和牙周炎）的基础。迫切需要抑制脂多糖（LPS）诱导的骨溶解的药物来预防感染性骨疾病中的骨质破坏。在本研究中，我们评估了从葛根（Pueraria lobata OHWI）根中分离出的天然异黄酮葛根素对LPS诱导的破骨细胞生成和骨质流失的影响。我们的体外研究表明，葛根素显著抑制LPS诱导的破骨细胞前体RAW264.7细胞向破骨细胞的分化。这种抑制是通过抑制破骨细胞激活因子肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和前列腺素E（PGE）的产生而发生的，这导致下调包括抗酒石酸酸性磷酸酶（TRAP）、组织蛋白酶K和基质金属蛋白酶9（MMP-9）在内的破骨细胞生成基因的mRNA表达。此外，LPS触发破骨细胞前体RAW264.7细胞中Akt的激活，而葛根素处理可抑制这种激活。在体内，葛根素减轻了小鼠颅骨骨溶解模型中LPS诱导的骨质流失。总体而言，葛根素可预防LPS诱导的破骨细胞形成、功能和骨质流失，其中对Akt激活的抑制起重要作用。这些发现提供了证据，表明葛根素作为预防和治疗细菌诱导的骨破坏疾病的有前景的候选药物可能是有益的，并为理解其可能的机制提供了新的见解。
