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

University Of Wisconsin-Milwaukee, Milwaukee WI

Investigators

Abstract

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.