Kitahara Keiichiro, Ishijima Muneaki, Rittling Susan R, Tsuji Kunikazu, Kurosawa Hisashi, Nifuji Akira, Denhardt David T, Noda Masaki
Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Endocrinology. 2003 May;144(5):2132-40. doi: 10.1210/en.2002-220996.
Intermittent PTH treatment increases cancellous bone mass in osteoporosis patients; however, it reveals diverse effects on cortical bone mass. Underlying molecular mechanisms for anabolic PTH actions are largely unknown. Because PTH regulates expression of osteopontin (OPN) in osteoblasts, OPN could be one of the targets of PTH in bone. Therefore, we examined the role of OPN in the PTH actions in bone. Intermittent PTH treatment neither altered whole long-bone bone mineral density nor changed cortical bone mass in wild-type 129 mice, although it enhanced cancellous bone volume as reported previously. In contrast, OPN deficiency induced PTH enhancement of whole-bone bone mineral density as well as cortical bone mass. Strikingly, although PTH suppressed periosteal bone formation rate (BFR) and mineral apposition rate (MAR) in cortical bone in wild type, OPN deficiency induced PTH activation of periosteal BFR and MAR. In cancellous bone, OPN deficiency further enhanced PTH increase in BFR and MAR. Analysis on the cellular bases for these phenomena indicated that OPN deficiency augmented PTH enhancement in the increase in mineralized nodule formation in vitro. OPN deficiency did not alter the levels of PTH enhancement of the excretion of deoxypyridinoline in urine, the osteoclast number in vivo, and tartrate-resistant acid phosphatase-positive cell development in vitro. These observations indicated that OPN deficiency specifically induces PTH activation of periosteal bone formation in the cortical bone envelope.
间歇性甲状旁腺激素（PTH）治疗可增加骨质疏松症患者的松质骨量；然而，它对皮质骨量的影响却多种多样。PTH促合成作用的潜在分子机制在很大程度上尚不清楚。由于PTH调节成骨细胞中骨桥蛋白（OPN）的表达，OPN可能是PTH在骨中的作用靶点之一。因此，我们研究了OPN在PTH骨作用中的作用。间歇性PTH治疗既未改变野生型129小鼠整个长骨的骨矿物质密度，也未改变皮质骨量，尽管如先前报道的那样它增加了松质骨体积。相比之下，OPN缺乏导致PTH使全骨骨矿物质密度以及皮质骨量增加。令人惊讶的是，尽管PTH抑制野生型皮质骨的骨膜骨形成率（BFR）和矿物质沉积率（MAR），但OPN缺乏导致PTH激活骨膜BFR和MAR。在松质骨中，OPN缺乏进一步增强了PTH对BFR和MAR的增加作用。对这些现象的细胞基础分析表明，OPN缺乏增强了PTH对体外矿化结节形成增加的促进作用。OPN缺乏并未改变PTH对尿中脱氧吡啶啉排泄的促进水平、体内破骨细胞数量以及体外抗酒石酸酸性磷酸酶阳性细胞的发育。这些观察结果表明，OPN缺乏特异性地诱导PTH激活皮质骨包膜中的骨膜骨形成。
