A Unique Peptide Containing the Heparin Binding Domain of IGFBP-2 Increases Bone Mass and Bone Formation in Ovariectomized (OVX) Rats
Presentation Number: OR05-5
Date of Presentation: April 3rd, 2017
Gang Xi*1, Christine Wai1, Thierry Abribat2, Thomas Delale2, Victoria DeMambro3, Clifford J Rosen3 and David R Clemmons1
1University of North Carolina at Chapel Hill, Chapel Hill, NC, 2Alize Pharma III, Ecully (Lyon), France, 3Maine Medical Center Research Institute, Scarborough, ME
Our previous studies showed IGFBP-2-/- mice had a significant reduction in BV/TV and a pegylated 13 amino acid peptide containing a unique heparin binding domain (HBDpeg) of IGFBP-2 stimulated bone acquisition. Thus, we determined if human HBDpeg could increase bone mass in wild type (WT), OVX rats. All animals were scanned by DEXA to obtain basal femoral areal bone mineral density (aBMD). Six sham and 6 OVX rats were sacrificed for basal femoral micro CT analysis. Sham or OVX (N=10/group) rats were randomized to receive control peptide or HBDpeg (6mg/kg) q80 hrs S.C. for 8 weeks. Four additional OVX groups (N=10/group) were treated with 0.7, 2.0, 6.0 mg/kg HBDpeg, or PTH (50 ug/kg/day). Two months post-surgery DEXA showed OVX femoral and tibial BMD were reduced 15.4±2.5% (p<0.001) and 10.7±2.6% (p<0.01), respectively, compared to sham. MicroCT showed BV/TV, connectivity and trabecular number in femoral trabecular bone were reduced 28.5±6.1% (p<0.05), 83.2±5.7% (p<0.01) and 48.7±6.5% (p<0.001), respectively, but trabecular spacing increased 148±50% (p<0.001). Control peptide treated OVX rats showed 16.0±7.4% (p<0.001) and 11.4±7.8% (p<0.01) decreases in femoral and tibial BMD by DEXA scanning, respectively, compared to Sham. After 8 weeks of treatment, PTH and 6 mg/kg HBDpeg increased femoral BMD 5.6±3.0% (p>0.05) and 6.2±2.4% (p<0.05) compared to control peptide. MicroCT showed OVX control peptide rats had 41.0%, 81.0% and 64.3% decreases in femoral trabecular BV/TV, connectivity and trabecular number, respectively, and 441% increase in trabecular spacing, compared to Sham. In OVX rats treatment with 6 mg/kg HBDpeg increased femoral BV/TV, connectivity and trabecular number 22.7±2.5% (p<0.001), 12.8%, 3.0%, respectively, whereas the increase in BV/TV with PTH vs control peptide was significantly lower: 9.2±4.0%. The 0.7 mg/kg and 2 mg/kg HBDpeg doses increased femoral trabecular BV/TV 16.7±3.2% (p<0.001) and 18.2±2.4% (p<0.001), respectively, compared to control peptide and significantly greater than the PTH treatment. Dynamic histomorphometry showed that the 0.7mg/kg group had a 121% greater increase in BFR compared to ctrl (1.04±0.39 vs 0.47±0.26; p<0.01) whereas PTH induced a 53% change. Our results clearly demonstrate that HBDpeg increased bone mass and stimulated BFR in the OVX rats and was more potent than PTH at the doses tested. The findings suggest that it may be an excellent candidate as an anabolic for treating osteoporosis and other bone diseases.
Disclosure: GX: Coinvestigator, Alize Pharma III. CW: Coinvestigator, Alize Pharma III. TA: Employee, Alize Pharma III. TD: Employee, Alize Pharma III. DRC: Principal Investigator, Alize Pharma III. Nothing to Disclose: VD, CJR