Male Igfbp2−/− mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2−/− mice do not have this phenotype but following ovariectomy (OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1 (0.7, 2, and 6 mg·kg^-1) and an OVX group receiving parathyroid hormone (PTH) (50 µg·kg^-1 per day). The peptides were administered for 8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density (aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4% (P < 0.01) compared to control peptide; similar to the increase noted with PTH (5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide (3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and 64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume (BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide (18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ± 10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose) and with PTH (25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate (MAR), bone formation rate/bone surface (BFR/BS), number of osteoblasts/bone perimeter (N.ob/B.pm), and decreased osteoclast surface/bone perimeter (Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.

雄性Igfbp2 - / -小鼠的骨量显着减少，含有这些胰岛素样生长因子结合蛋白2（IGFBP-2）受体结合域的肽的给药会刺激这些动物的骨形成。雌性Igfbp2-/-小鼠没有这种表型，但是卵巢切除术（OVX）后的骨骼损失比OVX野生型小鼠的骨骼多。这表明在缺乏雌激素的情况下，需要IGFBP-2来维持骨量。因此，进行了这些研究以确定该肽是否可以刺激OVX大鼠的骨获取。OVX大鼠分为七个治疗组：假动物，OVX动物，接受对照加扰肽的OVX动物或称为PEG-HBD-1的三剂活性肽（0.7、2和6 mg·kg ^-1之一））和接受甲状旁腺激素（PTH）（50 µg·kg ^-1的OVX组） 每天）。将肽施用8周。DXA显示OVX后股骨和胫骨面骨矿物质密度（aBMD）显着降低，而高剂量肽治疗使aBMD升高6.2％±2.4％（P  <0.01）。与PTH的增加幅度相似（5.6％±3.0％，P  <0.01）。两种较低剂量的肽也有类似的增加（低剂量为3.8％±1.5％，P  <0.05；低剂量为3.1％±1.6％，P =中剂量为0.07）。Micro CT显示，OVX对照肽动物的股骨小梁BV / TV和小梁数目分别减少了41％和64％。三种剂量的肽均显着增加了骨体积/总体积（BV / TV），而低剂量和中剂量则增加了骨小梁数目。每种肽剂量的皮质BV / TV和中轴厚度均显着增加（低剂量时分别为18.9％±9.8％，P  <0.01和14.2％±7.9％，P  <0.01; 23.7％±10.7％，P  <0.001和 中剂量为15.8％±6.1％，P <0.001;中剂量为19.0％±6.9％，P  <0.01和16.2％±9.7％， 高剂量为P <0.001）并伴有PTH（25.8％±9.2％，P <0.001和19.4％±8.8％，P  <0.001）。组织形态计量学表明，肽刺激的BV / TV的最低剂量，小梁厚度，矿物质沉积率（MAR），骨形成率/骨表面（BFR / BS），成骨细胞数/骨周长（N.ob / B.pm） ，破骨细胞表面/骨周长（Oc.S / B.Pm）降低。最高剂量刺激了除MAR和BFR / BS以外的所有这些参数。因此，IGFBP-2的肝素结合结构域受体区域解释了其在骨骼中的合成代谢活性。重要的是，该肽增强了雌激素缺乏动物的骨量。