Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Center for Childhood Cancer and Blood Disease, The Research institute at Nationwide Children's Hospital, Columbus, OH.
Spine (Phila Pa 1976). 2018 Jun 1;43(11):E616-E624. doi: 10.1097/BRS.0000000000002439.
In vitro and in vivo assessment of osteogenic effect by prostacyclin agonist (ONO-1301).
The aim of this study was to investigate the effects of ONO-1301 on in vitro osteoblastic differentiation and in vivo bone formation induced by bone morphogenetic protein (BMP).
Among prostaglandins (PGs), PGE2 is the most abundant in bone tissue and its effects on bone formation have been well studied. PGI2 (prostacyclin) is the second most abundant PG in bone tissue and plays important roles in hemodynamics. However, the effects of PGI2 on osteoblast differentiation and bone regeneration have not been elucidated.
The effects of PGI2 agonist (ONO-1301), with and without recombinant human (rh) BMP-2, on osteoblastic differentiation and cell proliferation were investigated in vitro using alkaline phosphatase (ALP) and WST-1 assays. Murine primary osteoblasts and cell lines (ST2, MC3T3-E1, C2C12, and CH310T1/2) were used for the study. The effects of ONO-1301 on rhBMP-2 induced bone formation were investigated in a mouse model of muscle pouch transplantation (ectopic model) and in a rat model of spinal fusion (orthotopic model).
ONO-1301 significantly increased ALP activity in the primary osteoblasts and ST2 cells. In addition, cotreatment with ONO-1301 and rhBMP-2 significantly increased ALP activity in the primary osteoblasts, as well as in ST2 and MC3T3-E1 cells. Cell proliferation was not affected by both ONO-1301 and ONO-1301 as well as rhBMP-2. In the ectopic model, ONO-1301 significantly increased the volume of ectopic bone whose formation was induced by BMP. In addition, in the orthotopic model, ONO-1301 significantly increased bone volume and fusion rate.
This study has demonstrated that the PG IP agonist ONO-1301 improves in vitro BMP-2 induced osteoblast differentiation and in vivo ectopic and orthotopic bone formation. The results suggest that ONO-1301 has a potential clinical application as an enhancer of BMP-induced bone formation.
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通过前列环素激动剂（ONO-1301）对成骨作用的体外和体内评估。
本研究旨在探讨 ONO-1301 对骨形态发生蛋白（BMP）诱导的体外成骨细胞分化和体内骨形成的影响。
在前列腺素（PGs）中，PGE2 在骨组织中含量最丰富，其对骨形成的影响已得到充分研究。PGI2（前列环素）是骨组织中第二丰富的 PG，在血液动力学中发挥重要作用。然而，PGI2 对成骨细胞分化和骨再生的影响尚未阐明。
采用碱性磷酸酶（ALP）和 WST-1 测定法，在体外研究 PGI2 激动剂（ONO-1301）联合和不联合重组人（rh）BMP-2 对成骨细胞分化和细胞增殖的影响。使用鼠原代成骨细胞和细胞系（ST2、MC3T3-E1、C2C12 和 CH310T1/2）进行研究。在肌肉囊移植（异位模型）和大鼠脊柱融合（原位模型）模型中研究了 ONO-1301 对 rhBMP-2 诱导的骨形成的影响。
ONO-1301 显著增加了原代成骨细胞和 ST2 细胞的 ALP 活性。此外，ONO-1301 与 rhBMP-2 共同处理也显著增加了原代成骨细胞以及 ST2 和 MC3T3-E1 细胞的 ALP 活性。ONO-1301 和 rhBMP-2 对细胞增殖均无影响。在异位模型中，ONO-1301 显著增加了由 BMP 诱导的异位骨体积。此外，在原位模型中，ONO-1301 显著增加了骨体积和融合率。
本研究表明，PG IP 激动剂 ONO-1301 可改善体外 BMP-2 诱导的成骨细胞分化和体内异位和原位骨形成。结果表明，ONO-1301 作为 BMP 诱导骨形成的增强剂具有潜在的临床应用前景。
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