I-Corps: Bone healing using a small-molecule therapeutic

I-Corps项目更广泛的影响/商业潜力是开发抗癌药物的替代应用，以促进骨愈合。虽然大多数骨折和骨损伤愈合良好，但在某些情况下，如骨质疏松症、糖尿病和老年，骨愈合机制受到阻碍，导致骨愈合受损。提出的技术将侧重于重新利用目前的抗癌药物来改善骨再生和/或防止骨质流失。这种药物能够通过增加骨量和骨矿物质密度来促进骨愈合。该机制也显示出在绝经患者雌激素减少引起的骨质疏松环境中预防骨质流失的潜力。目前，市场上所有的骨愈合药物都以骨细胞为目标，增加骨形成或减少骨吸收，但收效甚微。提议的药物通过增加间充质干细胞的成骨能力来靶向它们。由于传统的抗癌药物在杀死肿瘤细胞的同时也会导致骨质流失，因此这些结果将具有重大意义，但该药物具有相反的作用，因为它可以保护骨骼。这个I-Corps项目是基于一种促进骨愈合的小分子治疗的发展。抗癌药物UC2288将重新用于该应用。骨通常在骨折后完全愈合，但在老年人等情况下，这一过程会发生实质性改变，导致骨愈合受阻、延迟或不愈合。这可能会导致骨骼生物力学的改变，导致其他并发症，并最终影响生活质量。已经确定间充质干细胞（MSCs）在骨愈合过程中起着至关重要的作用，在老年等病例中，MSCs会降低骨形成能力。目前的治疗策略侧重于下游成骨因素，往往显示有限的成功。先前的研究已经证明了细胞周期调节因子p21与骨愈合之间的联系，其中p21表达的减少与损伤后骨形成的增加有关。为了将这些发现应用于临床，我们测试了UC2288降低p21表达的功效。结果表明，UC2288可降低人和小鼠间充质干细胞中p21的表达，增加成骨基因的表达。此外，UC2288的体内作用也得到了证实，注射UC2288可以增加小鼠横向骨折后的骨体积和表面积。在骨折部位使用所建议的药物，可能会改善骨愈合和患者预后。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of alternate applications for an anti-cancer drug to promote bone healing. While most fractures and bone injuries heal well, in some cases such as osteoporosis, diabetes, and advanced age, the bone healing mechanism is hampered leading to compromised bone healing. The proposed technology will focus on repurposing a current anti-cancer drug for improving bone regeneration and/or preventing bone loss. This drug is able to enhance bone healing by increasing bone volume and bone mineral density. The mechanism also has shown potential to prevent the loss of bone in an osteoporotic environment induced by loss of estrogen in patients with menopause. Currently, all drugs for bone healing on the market target bone cells to increase bone formation or reduce bone resorption with limited success. The proposed drug targets mesenchymal stem cells by increasing their osteogenic capacity. These results would be of significant interest as conventional anti-cancer drugs also induce bone loss while killing tumor cells, but the proposed drug has the opposite effect in that it protects bone.This I-Corps project is based on the development of a small molecule therapeutic to promote bone healing. The anti-cancer drug, UC2288, will be repurposed for this application. Bones typically heal completely after fracture, but in cases such as advanced age, this process is substantially altered resulting in hampered and delayed healing or non-union of bone. This may result in changes in biomechanics of the bone leading to other complications and ultimately affect quality of life. It has been established that mesenchymal stem cells (MSCs) play a vital role in the bone healing process, and in cases like advanced age, MSCs have reduced bone forming capacity. Current treatment strategies focus on downstream osteogenic factors, often showing limited success. Previous research has demonstrated a link between the cell cycle regulator p21 and bone healing where reduced expression of p21 has been linked to increased bone formation after injury. To translate these findings to the clinic, efficacy of UC2288 was tested in reducing p21 expression. It was shown that UC2288 may reduce p21 expression and increase expression of osteogenic genes in both human and murine mesenchymal stem cells. In addition, in vivo efficacy of UC2288 was shown where injections of UC2288 increased bone volume and surface area in mice after a transverse fracture. Using the proposed drug at the site of fracture, it may be possible to improve bone healing and patient outcomes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.