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

这个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、糖尿病和高龄，骨愈合机制受到阻碍，导致骨愈合受损。 这项技术将专注于重新利用目前的抗癌药物来改善骨再生和/或预防骨丢失。 这种药物能够通过增加骨体积和骨矿物质密度来增强骨愈合。该机制还显示出预防绝经期患者雌激素丢失引起的骨质疏松环境中的骨丢失的潜力。 目前，市场上所有用于骨愈合的药物都靶向骨细胞以增加骨形成或减少骨吸收，但成功率有限。该药物通过增加间充质干细胞的成骨能力来靶向间充质干细胞。 这些结果将是非常有趣的，因为传统的抗癌药物在杀死肿瘤细胞的同时也会引起骨丢失，但拟议的药物具有相反的作用，因为它保护骨。这个I-Corps项目是基于开发一种小分子治疗剂来促进骨愈合。 抗癌药物UC 2288将重新用于该应用。 骨通常在骨折后完全愈合，但在诸如高龄的情况下，该过程被显著改变，导致骨的愈合受阻和延迟或不愈合。这可能导致骨生物力学的变化，从而导致其他并发症，并最终影响生活质量。已经确定，间充质干细胞（MSC）在骨愈合过程中起着至关重要的作用，在老年等情况下，MSC的骨形成能力降低。目前的治疗策略集中在下游成骨因子，往往表现出有限的成功。 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。 为了将这些发现转化为临床，测试了UC 2288在降低p21表达方面的功效。结果表明，UC 2288可以降低人和鼠间充质干细胞中p21的表达，并增加成骨基因的表达。此外，显示了UC 2288的体内功效，其中注射UC 2288增加了小鼠在横向骨折后的骨体积和表面积。 在骨折部位使用拟议的药物，有可能改善骨愈合和患者的预后。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.