Wang Yongmei, Nishida Shigeki, Boudignon Benjamin M, Burghardt Andrew, Elalieh Hashem Z, Hamilton Michelle M, Majumdar Sharmila, Halloran Bernard P, Clemens Thomas L, Bikle Daniel D
Department of Medicine, Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
J Bone Miner Res. 2007 Sep;22(9):1329-37. doi: 10.1359/jbmr.070517.
We showed that the IGF-IR-null mutation in mature osteoblasts leads to less bone and decreased periosteal bone formation and impaired the stimulatory effects of PTH on osteoprogenitor cell proliferation and differentiation.
This study was carried out to examine the role of IGF-I signaling in mediating the actions of PTH on bone.
Three-month-old mice with an osteoblast-specific IGF-I receptor null mutation (IGF-IR OBKO) and their normal littermates were treated with vehicle or PTH (80 microg/kg body weight/d for 2 wk). Structural measurements of the proximal and midshaft of the tibia were made by microCT. Trabecular and cortical bone formation was measured by bone histomorphometry. Bone marrow stromal cells (BMSCs) were obtained to assess the effects of PTH on osteoprogenitor number and differentiation.
The fat-free weight of bone normalized to body weight (FFW/BW), bone volume (BV/TV), and cortical thickness (C.Th) in both proximal tibia and shaft were all less in the IGF-IR OBKO mice compared with controls. PTH decreased FFW/BW of the proximal tibia more substantially in controls than in IGF-IR OBKO mice. The increase in C.Th after PTH in the proximal tibia was comparable in both control and IGF-IR OBKO mice. Although trabecular and periosteal bone formation was markedly lower in the IGF-IR OBKO mice than in the control mice, endosteal bone formation was comparable in control and IGF-IR OBKO mice. PTH stimulated endosteal bone formation only in the control animals. Compared with BMSCs from control mice, BMSCs from IGF-IR OBKO mice showed equal alkaline phosphatase (ALP)(+) colonies on day 14, but fewer mineralized nodules on day 28. Administration of PTH increased the number of ALP(+) colonies and mineralized nodules on days 14 and 28 in BMSCs from control mice, but not in BMSCs from IGF-IR OBKO mice.
Our results indicate that the IGF-IR null mutation in mature osteoblasts leads to less bone and decreased bone formation, in part because of the requirement for the IGF-IR in mature osteoblasts to enable PTH to stimulate osteoprogenitor cell proliferation and differentiation.
我们发现成熟成骨细胞中的胰岛素样生长因子-1受体（IGF-IR）无效突变导致骨量减少、骨膜骨形成降低，并损害甲状旁腺激素（PTH）对骨祖细胞增殖和分化的刺激作用。
本研究旨在探讨IGF-I信号在介导PTH对骨作用中的作用。
对3月龄具有成骨细胞特异性IGF-I受体无效突变的小鼠（IGF-IR OBKO）及其正常同窝小鼠给予赋形剂或PTH（80微克/千克体重/天，共2周）。通过显微CT对胫骨近端和骨干进行结构测量。通过骨组织形态计量学测量小梁骨和皮质骨形成。获取骨髓间充质干细胞（BMSC）以评估PTH对骨祖细胞数量和分化的影响。
与对照组相比，IGF-IR OBKO小鼠胫骨近端和骨干的归一化骨无脂重量（FFW/BW）、骨体积（BV/TV）和皮质厚度（C.Th）均较低。PTH使对照组胫骨近端的FFW/BW降低幅度比IGF-IR OBKO小鼠更大。PTH处理后，对照组和IGF-IR OBKO小鼠胫骨近端C.Th的增加幅度相当。虽然IGF-IR OBKO小鼠的小梁骨和骨膜骨形成明显低于对照小鼠，但对照小鼠和IGF-IR OBKO小鼠的骨内膜骨形成相当。PTH仅刺激对照动物的骨内膜骨形成。与对照小鼠的BMSC相比，IGF-IR OBKO小鼠的BMSC在第14天显示出等量的碱性磷酸酶（ALP）（+）集落，但在第28天矿化结节较少。给予PTH增加了对照小鼠BMSC在第14天和第28天的ALP（+）集落数量和矿化结节数量，但未增加IGF-IR OBKO小鼠BMSC的相应数量。
我们的结果表明，成熟成骨细胞中的IGF-IR无效突变导致骨量减少和骨形成降低，部分原因是成熟成骨细胞中需要IGF-IR以使PTH能够刺激骨祖细胞增殖和分化。
