Mevalonates Restore Zoledronic Acid-induced Osteoclastogenesis Inhibition
Mevalonates Restore Zoledronic Acid-induced Osteoclastogenesis Inhibition
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DOI：
10.1177/0022034514564187
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发表时间：
2015-04-01
影响因子：
7.6
通讯作者：
Okabe, K.
中科院分区：
文献类型：
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作者：
Nagaoka, Y.;Kajiya, H.;Okabe, K.
双膦酸盐相关性颌骨坏死（BRONJ）可能是由于长期服用含氮双膦酸盐（NBPs）的患者手术治疗后骨愈合持续不完善引起的。NBPs通过破坏破骨细胞的甲羟戊酸甾醇途径抑制破骨细胞骨吸收。因此，我们假设外源性甲羟戊酸代谢物恢复了NBPs对破骨细胞发生和骨重塑的抑制作用。为了阐明甲羟戊酸代谢物，尤其是香叶基焦磷酸（GGPP）和香叶基转移酶底物香叶基酸（GGOH）的作用，我们研究了唑来膦酸加或不加GGOH或GGPP对牙槽内破骨细胞分化、多核和骨矿物沉积的影响。唑来膦酸可减少经核因子- b配体受体激活剂和巨噬细胞集落刺激因子处理的小鼠破骨细胞前体产生的酒石酸抗性酸性磷酸酶（TRAP）阳性多核细胞的数量。唑来膦酸不仅能同时抑制TRAP、组织蛋白酶K、降钙素受体、空泡h - atp酶等破骨细胞分化相关分子的表达，还能同时抑制多核相关分子如树突细胞表达的7跨膜蛋白和破骨细胞刺激跨膜蛋白的表达。GGOH或GGPP处理，而不是法尼酯酸处理，恢复了唑来膦酸抑制的trap阳性多核细胞数量以及这些分子的表达。虽然小鼠腹腔注射唑来膦酸和脂多糖似乎会诱导bronj样病变伴空骨陷窝，并减少拔牙槽内的矿物沉积，但GGOH和GGPP都能部分恢复对唑来膦酸相关矿物沉积的抑制作用。这些结果提示甲羟戊酸代谢物作为BRONJ的治疗药物的潜力。
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranylgeranyl transferase substrate geranylgeranyl acid (GGOH), we examined the effects of zoledronic acid with or without GGOH or GGPP on osteoclast differentiation, multinucleation, and bone mineral deposition in tooth-extracted sockets. Zoledronic acid decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from mouse osteoclast precursors treated with receptor activator of nuclear factor-B ligand and macrophage colony-stimulating factor. Zoledronic acid simultaneously suppressed not only the expressions of osteoclastic differentiation-related molecules such as TRAP, cathepsin K, calcitonin receptor, and vacuolar H-ATPase but also those of multinucleation-related molecules such as dendrocyte-expressed 7 transmembrane proteins and osteoclast stimulatory transmembrane protein. Treatment with GGOH or GGPP, but not farnesyl acid, restored the zoledronic acid-inhibited number of TRAP-positive multinuclear cells together with the expressions of these molecules. Although intraperitoneal administration of zoledronic acid and lipopolysaccharide into mice appeared to induce BRONJ-like lesions with empty bone lacunae and decreased mineral deposition in tooth-extracted socket, both GGOH and GGPP partially restored the inhibitory effects on zoledronic acid-related mineral deposition. These results suggest the potential of mevalonic acid metabolites as therapeutic agents for BRONJ.