Bone Abstracts

Introduction: A synthetic prostacyclin IP receptor agonist (ONO-1301) has been reported to induce the production of endogenous HGF and VEGF in fibroblasts by stimulating cAMP production.

Materials and methods: In vitro; murine primary osteoblasts and cell line (ST2, MC3T3-E1, C2C12) were treated with BMP-2 (0–100 ng/ml) and ONO-1301 (0–10⁻⁶ M). ALP assay and cell proliferation assay were performed. In vivo analysis, Collagen pellets containing BMP-2 (1 μg/3 μg) w/ or w/o ONO-1301 were implanted into the dorsal muscle pouch of mice (n=32), and BV by μCT at 3 weeks after operation were evaluated. In a rat spinal fusion model, SD rats (n=20) were treated with 0.5 μg of BMP-2 w/ or w/o ONO-1301, and fusion rates and newly formed BV were evaluated by micro CT every week until post-op. 6w. A manual palpation test was performed.

Results: Treatment of ONO-1301 significantly increased ALP activities on primary osteoblasts and ST2. And the co-administration with BMP-2 further enhanced the effects in primary osteoblasts, ST2 and MC3T3-E1. Cell proliferation was not affected by the administration of ONO-1301. In a mouse transplantation model, ONO-1301 administration significantly increased BV when co-transplanted with 1 μg of BMP-2 (BV [w/o ONO-1301 v.s. w/ ONO-1301; 4.3±2.8 mm³ vs 7.0±3.9 mm³, P=0.05). In a rat spinal fusion model, ONO-1301 significantly increased the BV of the newly formed bone at 4–5 weeks after operation (4w; 3.7±1.5 mm³ vs 5.2±1.5 mm³; P=0.01, 5w; 3.4±1.4 mm³ vs 4.8±1.5 mm³; P<0.05). In addition, ONO-1301 significantly increased the fusion rates (w/o ONO-1301:30% vs w/ ONO-1301:70%, P<0.05) and fusion analysis with a manual palpation test (w/o ONO-1301: 30%, w/ ONO-1301: 66.6% vs, P<0.05).

Conclusions: ONO-1301 significantly increased osteoblastic differentiation in vitro, and significantly enhanced ectopic and orthotopic bone formation in vivo. These results suggest that ONO-1301 has a potential to be used as a bone graft substitute or bone fusion enhancer in a clinical setting.