Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts.
Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts.
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发表时间：
2000-11
期刊：
影响因子：
11.2
通讯作者：
Gregory G. Reinholz;B. Getz;Larry Pederson;Emily S. Sanders;M. Subramaniam;J. Ingle;T. Spelsberg
中科院分区：
文献类型：
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作者：
Gregory G. Reinholz;B. Getz;Larry Pederson;Emily S. Sanders;M. Subramaniam;J. Ingle;T. Spelsberg
双膦酸盐在临床上广泛用于治疗骨吸收过度的骨疾病。然而，双膦酸盐对骨的作用机制尚未完全了解。双磷酸盐对骨骼的直接作用的研究主要限于它们对骨吸收破骨细胞的影响，这意味着某些活性可能是通过骨形成成骨细胞产生的旁分泌因子间接介导的。关于双膦酸盐对成骨细胞的直接影响知之甚少。在这份报告中，几个双膦酸盐对细胞增殖，基因表达和骨形成培养的人胎儿成骨细胞的直接行动进行了检查。成骨细胞增殖减少，并以剂量依赖性的方式增加细胞分化与双膦酸帕米膦酸盐处理的文化。此外，帕米膦酸盐治疗增加了成骨细胞的总细胞蛋白，碱性磷酸酶活性和I型胶原分泌。与上述发现一致，在用帕米膦酸盐培养的成骨细胞中骨形成速率也增加。另外两种双膦酸盐，弱作用的依替膦酸盐和有效的新类似物唑来膦酸盐的作用也与帕米膦酸盐对永生化人胎儿成骨细胞（hFOB）增殖和骨形成速率的作用进行了比较。帕米磷酸钠和唑来磷酸钠以相同的效力降低hFOB细胞增殖，而依替磷酸钠仅在更高的浓度下才降低增殖。比较EDTA和依替膦酸盐的研究表明，依替膦酸盐可能通过降低游离二价离子浓度间接作用于hFOB细胞，而帕米膦酸盐和唑来膦酸盐似乎通过直接作用于hFOB细胞。帕米膦酸盐和唑来膦酸盐均增加hFOB细胞骨形成，而依替膦酸盐和EDTA未观察到增加。综上所述，这些观察结果强烈表明，帕米膦酸盐或唑来膦酸盐治疗增强成骨细胞的分化和骨形成活性。
Bisphosphonates are widely used clinically to treat bone diseases in which bone resorption is in excess. However, the mechanism of bisphosphonate action on bone is not fully understood. Studies of direct action of bisphosphonates on bone have been limited mainly to their effects on bone-resorbing osteoclast cells, with implications that some activity may be mediated indirectly through paracrine factors produced by the bone-forming osteoblast cells. Little is known about the direct effects of bisphosphonates on osteoblasts. In this report, the direct actions of several bisphosphonates on cell proliferation, gene expression, and bone formation by cultured human fetal osteoblasts were examined. Osteoblast cell proliferation was decreased, and cytodifferentiation was increased in a dose-dependent manner in cultures treated with the bisphosphonate pamidronate. In addition, pamidronate treatment increased total cellular protein, alkaline phosphatase activity, and type I collagen secretion in osteoblasts. Consistent with the above-mentioned findings, the rate of bone formation was also increased in osteoblasts cultured with pamidronate. The actions of two other bisphosphonates, the weak-acting etidronate and the potent new analogue zoledronate, were also compared with the action of pamidronate on proliferation of immortalized human fetal osteoblast (hFOB) cells and rate of bone formation. Pamidronate and zoledronate decreased hFOB cell proliferation with equal potency, whereas etidronate decreased proliferation only at much higher concentrations. Studies comparing EDTA and etidronate indicate that etidronate may act indirectly on the hFOB cells by reducing free divalent ion concentrations, whereas pamidronate and zoledronate appear to act on the hFOB cells by a direct action. Both pamidronate and zoledronate increase hFOB cell bone formation, whereas no increase is observed with etidronate and EDTA. Taken together, these observations strongly suggest that treatment with pamidronate or zoledronate enhances the differentiation and bone-forming activities of osteoblasts.