A Novel Osteoinductive Molecule in Bone Regeneration

描述（由申请人提供）：由于骨缺损的再生能力有限，因此在颅颌面创伤和先天性颅颌面畸形的重建手术中植骨的重要性得到了广泛认可。为了避免与自体骨移植收获相关的发病率，骨诱导分子如骨形态发生蛋白（BMP）的应用已被深入研究。 我们已经确定了一种新的骨诱导分子，它直接受到核心结合因子a1的调控，核心结合因子a1是成骨细胞形成和功能的关键介质。在体外的分子过表达显着增加成骨细胞的分化和矿化，而在体内的过表达显着增加转基因动物的颅骨缝过早骨形成。比较新分子与等效剂量的BMP 2的初步研究表明，在大鼠颅骨缺损模型中的骨再生水平相当。有趣的是，我们的体外数据还表明新分子和BMP 2对碱性磷酸酶活性诱导的加和或协同作用。 为了确定这种分子是否可以可行地替代或补充现有的骨诱导分子如BMP，我们提出了这个I期研究：1）确认分子在骨再生中的功效; 2）确定在大鼠颅骨临界尺寸缺损模型中使用该分子、BMP 2或BMP 7进行骨再生的最佳剂量; 3）比较颅骨缺损模型中的最佳剂量;和4）评价商业骨传导载体与我们的分子组合在骨再生中的功效。 第一阶段的完成将允许对特定陶瓷载体内的BMP基准分析分子的骨诱导能力。II期研究将集中在BMP替代疗法和BMP辅助疗法两个不同领域的进一步分子开发，并为最终产品商业化提供基础。我们的长期目标是开发一种有效的自体骨替代物。

DESCRIPTION (provided by applicant): Because bony defects have limited regenerative capability, the importance of bone grafting during reconstructive surgery for craniomaxilofacial trauma and congenital craniofacial anomalies is widely recognized. To avoid the morbidity associated with autologous bone graft harvest, application of osteoinductive molecules such as the bone morphogenetic proteins (BMPs) has been intensively studied. We have identified a novel osteoinductive molecule that is directly regulated by core-binding factor a1, a critical mediator of osteoblast formation and function. Molecule overexpression in vitro significantly increased osteoblast differentiation and mineralization, while overexpression in vivo significantly increased premature bone formation in the calvarial sutures of transgenic animals. Pilot studies comparing the novel molecule to an equivalent dose of BMP2 demonstrated comparable levels of bone regeneration in a rat calvarial defect model. Interestingly, our in vitro data also suggest an additive or synergistic effect between the novel molecule and BMP2 on induction of alkaline phosphatase activity. To determine if this molecule can feasibly replacement or complement existing osteoinductive molecules such as BMPs, we propose this Phase I study to: 1) confirm molecule efficacy in bone regeneration; 2) determine optimal dosages for bone regeneration using the molecule, BMP2, or BMP7 in a rat calvarial critical size defect model; 3) compare optimized dosages in the calvarial defect model; and 4) evaluate the efficacy of a commercial osteoconductive carrier combined with our molecule in bone regeneration. Phase I completion will allow analyses of the molecule's osteoinductive capacity against a BMP benchmark within a specific ceramic carrier. Phase II studies will focus on further molecule development in two distinct areas of BMP replacement therapy and BMP adjunct therapy and provide the foundation for eventual product commercialization. Our long term goal is to develop an effective autograft bone substitute.