A peptide containing the receptor binding site of insulin-like growth factor binding protein-2 enhances bone mass in ovariectomized rats

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