Accelerated Healing of Traumatic Fractures and Nonunion
Abstract
Our combat military faces many dangers not least of which is skeletal damage due to trauma. Perhaps the most challenging of these traumatic events are fractures whose healing is substantially prolonged. In fact, healing of high energy leg fractures average approximately 1 year. More disturbing, 10%-20% of fractures fail to spontaneously heal resulting in “nonunions,” which cause severe disabilities. Nonunions are generally treated by implanting (grafting) bone taken from the patient’s pelvis into the nonunion. This approach is associated with morbidities related to the harvesting procedure such as prolonged pain, failure to heal the pelvis, and infection. In addition, the amount of bone that can be harvested and grafted is limited. There is a compelling need to develop effective therapies to treat nonunions frequently induced in our combat military. There are basically two types of nonunions. The first, known as defect nonunion, is due to a loss of connecting bone typically due to trauma. The second is biological failure of bone to heal. We reasoned that markedly enhancing the capacity of the skeleton to produce bone may therefore accelerate nonunion healing in both circumstances. With this in mind, we extended our work on the relationship of obesity and the skeleton and produced a mouse that lacks fat by targeting a protein called adiponectin that characterizes fat and related cells, some of which develop the capacity to produce bone. Surprisingly, the amount of bone in these fat-depleted mice increases 10-fold (1000%) within 2 weeks, providing the most rapid and profound bone formation ever observed. While ablating fat in people is not a reasonable therapeutic approach to treat nonunion, we reasoned that understanding the mechanism by which fat-depleted mice markedly increase their amount of bone could provide the basis for developing a very potent bone-stimulating drug to accelerate fracture healing. To understand the mechanism by which fat-depleted mice increase their bone, we looked at the genes, in bone, which are activated or suppressed. Two genes, namely gremlin 1 (GREM1) and chordin like protein 1 (CHRDL1) were among those most suppressed. Importantly, both genes block a molecule known as bone morphogenetic protein receptor (BMPR) that, when activated, stimulates bone formation. Thus, we propose that the absence of the inhibitory effects of GREM1 and CHRDL1 on BMPR markedly stimulates bone formation. If true, a drug that blocks GREM1 and CHRDL1 could be effective in promoting nonunion healing. In addition to the need of a uniquely potent bone stimulating drug, a great deal of attention has focused on the possibility that implantation of early stem cells that ultimately form bone into nonunions could replace bone grafts and be at least as effective. In fact, we have confirmed that early stem cells, in fat-depleted mice, mature into bone-forming cells much more rapidly and robustly than those in control mice. Our preliminary data provide a mechanistic theory that could lead to development of a potent bone-forming drug and identify a stem cell that could replace and perhaps supersede the capacity of implanted bone grafts to heal nonunions. The first aspect of our proposal is to determine the skeletal effects of GREM1 and CHRDL1, which inhibit BMPR. To this end, we will first confirm they meaningfully suppress bone formation. To this end, we will synthesize the proteins and inject them into fat-depleted mice. If the marked increase in bone mass of these mice is prevented by GREM1 and CHRDL1, it would confirm they inhibit bone formation. To confirm this conclusion and importantly provide a rationale for drug development, we will ask what happens when we delete these inhibitors? Thus, we will selectively delete GREM1 and CHRDL1 genes in cells, which produce the fat-associated protein, adiponectin. Enhanced bone formation would provide strong evidence supporting the possibility that medicinal GREM1 and CHRDL1 sup
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110385
Entities
People
- Steven Teitelbaum
Organizations
- United States Army
- Washington University in St. Louis