By studying the underlying differences in gene expression during healing after a bone break in young versus aged mice, Jaimo Ahn, MD, PhD, assistant professor of Orthopaedic Surgery at the Perelman School of Medicine, University of Pennsylvania, and his colleagues aim to find specific pathways of fracture healing in humans. The team of researchers presented their findings in a poster presentation at the 2013 American Academy of Orthopedic Surgeons annual meeting in Chicago.
Problems with healing after bone fractures in elderly patients can be attributed, in part, to the compromised function of certain stem cells, called MSCs, that participate in the mending of the fracture. MSCs (Mesenchymal stem cells), can differentiate into a variety of cell types: cartilage, fat and – most notably in fractures – bone cells.
An important pathway – called Notch, for the name of the receptor that is critical in relaying the “signal” – has been identified as a critical event in the healing of non-skeletal tissues in an age-dependent manner. In the new study, the Penn team suspected that Notch would play a vital role in healing aged broken bones.
The team characterized fracture healing as a function of age and time post fracture in laboratory mice. Five-month-old laboratory mice are reproductively and skeletally mature. At 25-months-old, mice of the same strain are considered “geriatric.” The researchers looked for progression of tissue and healing and the expression of Notch pathway genes including the ligands (small molecules that bind Notch to spur it into action), as well as Notch receptors and their down-stream effects. They examined both the healing fracture itself as well as the MSCs from the two age groups.
The team found that young mice produce a more robust healing response (timing, quantity and quality) than geriatric mice which persisted throughout healing. Interestingly, base line levels of Notch signaling are reduced in MSCs from geriatric mice. However, MSCs from young and old mice are both able to be stimulated by Jagged1 (one of the main ligands of Notch).
“The Notch signaling pathway’s importance in skeletogenesis combined with our data showing reduced baseline Notch activity in geriatric MSCs and the ability of the MSCs to respond to Jagged1 provides a rational basis for delivery of Jagged1 as a potential therapeutic option for aged fractures” says Dr Ahn.
Importantly, this model provides a validated system for further study of the age-dependent differences in fracture healing – and to test alterations that will enhance that healing for years to come.
Poster P480/P480: Notch Signaling in Mesenchymal Stem Cells (MSCs) and Tibial Fracture Callus Harvested from Geriatric Mice
Additional Penn authors include Kurt Hankenson, DVM, PhD, Nicole Belkin, MD, Luke Lopas, Lorraine Mutyaba, and Lee McDaniel.
University of Pennsylvania School of Medicine