Abstract
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.
Highlights
Insulin-like growth factor binding protein-2(IGFBP-2) is a high affinity form of an insulin-like growth factor (IGF)-binding protein and has the capacity to regulate the amount of IGF-I and IGF-II
The analysis showed that low dose of the PEGHBD1 peptide resulted in a statistically significantly greater bone volume/total volume (BV/TV) (e.g. 32% ± 2%) compared to control peptide-treated OVX animals (e.g., 27% ± 1%) (Fig. 2b)
Our initial studies conducted in Igfbp2 −/− mice showed that only male mice developed a low bone mass phenotype.[9]
Summary
Insulin-like growth factor binding protein-2(IGFBP-2) is a high affinity form of an insulin-like growth factor (IGF)-binding protein and has the capacity to regulate the amount of IGF-I and IGF-II that are transported out of the vasculature, and able to interact with cell surface receptors.[1]. A synthetic peptide containing this core 13 amino acid sequence activates the RPTPβ linked pathway and promotes bone acquisition in vivo.[6,8] The importance of these findings was demonstrated in male Igfbp2 −/− mice that had reduced areal bone mass, decreased trabecular bone volume/total volume (BV/TV), and low bone turnover.[9] Administration of the 13 AA peptide enhanced bone formation and inhibited bone resorption in Igfbp2−/− mice.[8] in contrast to males, female mice did not exhibit this phenotype To further investigate this difference, we prepared female Igfbp2 −/− mice with and without ovariectomy (OVX) and compared the degree of bone loss to wild-type C57BL6J control and ovariectomized mice.[10] OVX in wild-type mice caused a significant reduction in BV/TV, trabecular number and increased trabecular spacing, the deletion of IGFBP-2 in ovariectomized mice caused a significantly greater decrease in trabecular BV/TV and reduced trabecular number in the proximal.
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