Reinholz G G, Getz B, Pederson L, Sanders E S, Subramaniam M, Ingle J N, Spelsberg T C
Department of Biochemistry and Molecullar Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Cancer Res. 2000 Nov 1;60(21):6001-7.
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.
双膦酸盐在临床上被广泛用于治疗骨吸收过度的骨疾病。然而，双膦酸盐对骨骼作用的机制尚未完全明确。双膦酸盐对骨骼直接作用的研究主要局限于其对骨吸收破骨细胞的影响，这意味着某些活性可能通过成骨细胞产生的旁分泌因子间接介导。关于双膦酸盐对成骨细胞的直接作用知之甚少。在本报告中，研究了几种双膦酸盐对培养的人胎儿成骨细胞的细胞增殖、基因表达和骨形成的直接作用。在用双膦酸盐帕米膦酸处理的培养物中，成骨细胞增殖减少，细胞分化呈剂量依赖性增加。此外，帕米膦酸处理增加了成骨细胞中的总细胞蛋白、碱性磷酸酶活性和I型胶原蛋白分泌。与上述发现一致，在用帕米膦酸培养的成骨细胞中骨形成率也增加。还比较了另外两种双膦酸盐，作用较弱的依替膦酸和强效新类似物唑来膦酸，与帕米膦酸对永生化人胎儿成骨细胞（hFOB）增殖和骨形成率的作用。帕米膦酸和唑来膦酸以相同效力降低hFOB细胞增殖，而依替膦酸仅在高得多的浓度下才降低增殖。比较EDTA和依替膦酸的研究表明，依替膦酸可能通过降低游离二价离子浓度间接作用于hFOB细胞，而帕米膦酸和唑来膦酸似乎通过直接作用于hFOB细胞。帕米膦酸和唑来膦酸均增加hFOB细胞的骨形成，而依替膦酸和EDTA则未观察到增加。综上所述，这些观察结果强烈表明，用帕米膦酸或唑来膦酸治疗可增强成骨细胞的分化和骨形成活性。
