Murakami H, Takahashi N, Sasaki T, Udagawa N, Tanaka S, Nakamura I, Zhang D, Barbier A, Suda T
Department of Biochemistry, School of Dentistry, Showa University, Tokyo, Japan.
Bone. 1995 Aug;17(2):137-44. doi: 10.1016/s8756-3282(95)00150-6.
The mechanism of action of tiludronate [(4-chlorophenyl)-thiomethylene bisphosphonate] on osteoclastic bone resorption was examined in mouse culture systems. Tiludronate did not inhibit the formation of osteoclast-like multinucleated cells (OCLs) induced by 1 alpha,25-dihydroxyvitamin D3 in cocultures of mouse osteoblastic cells and bone marrow cells. OCLs obtained from cocultures on collagen gel-coated dishes, treated with tiludronate, formed as many resorption pits on dentine slices as those obtained from the control cocultures. However, pit formation by OCLs was dose-dependently inhibited when tiludronate was added directly to the pit formation assay. Other bisphosphonates such as alendronate and etidronate dose-dependently inhibited pit formation according to the in vivo potencies of the respective bisphosphonates to inhibit bone resorption. However, they had no inhibitory effect on the recruitment of OCLs induced by 1 alpha,25-dihydroxyvitamin D3 in the cocultures. When OCLs were placed on dentine slices, they formed the ringed structure of F-actin-containing podosomes and ruffled borders (polarized OCLs) even in the presence of tiludronate. However, the actin rings in OCLs were disrupted by the addition of tiludronate soon after they began to resorb dentine. In contrast, OCLs placed on collagen gel formed neither actin rings nor ruffled borders (nonpolarized OCLs), and showed no response to tiludronate. OCLs formed from the spleen cells of osteosclerotic (oc/oc) mice developed the ringed structure of podosomes, but not ruffled borders, on dentine slices. The actin ring in the oc/oc spleen cell-derived OCLs placed on dentine slices was not disrupted by the addition of tiludronate.(ABSTRACT TRUNCATED AT 250 WORDS)
在小鼠培养系统中研究了替鲁膦酸[（4-氯苯基）-硫亚甲基双膦酸酯]对破骨细胞性骨吸收的作用机制。在小鼠成骨细胞和骨髓细胞共培养体系中，替鲁膦酸不抑制1α,25-二羟基维生素D3诱导的破骨细胞样多核细胞（OCLs）的形成。从胶原凝胶包被培养皿上的共培养物中获得的OCLs，用替鲁膦酸处理后，在牙本质切片上形成的吸收陷窝数量与对照共培养物获得的OCLs形成的吸收陷窝数量相同。然而，当直接将替鲁膦酸添加到陷窝形成试验中时，OCLs形成陷窝的能力呈剂量依赖性受到抑制。其他双膦酸盐如阿仑膦酸和依替膦酸根据各自双膦酸盐体内抑制骨吸收的效力呈剂量依赖性抑制陷窝形成。然而，它们对共培养物中1α,25-二羟基维生素D3诱导的OCLs募集没有抑制作用。当OCLs置于牙本质切片上时，即使存在替鲁膦酸，它们也会形成含F-肌动蛋白的足突体和皱褶缘的环状结构（极化OCLs）。然而，OCLs开始吸收牙本质后不久，添加替鲁膦酸会破坏OCLs中的肌动蛋白环。相反，置于胶原凝胶上的OCLs既不形成肌动蛋白环也不形成皱褶缘（非极化OCLs），并且对替鲁膦酸无反应。由骨硬化（oc/oc）小鼠的脾细胞形成的OCLs在牙本质切片上形成足突体的环状结构，但不形成皱褶缘。置于牙本质切片上的oc/oc脾细胞来源的OCLs中的肌动蛋白环不会因添加替鲁膦酸而被破坏。（摘要截短于250字）
