Mechanisms Responsible for Bone Loss in Osteomyelitis

/Abstract Background and Innovation. The goal of this project is to uncover the mechanisms that cause rapid bone loss in osteomyelitis, which is an infection of bone that has adverse consequences for many patients treated by the Veterans healthcare system. Due in part to the loss of skeletal integrity, the infected limb or digit must often be amputated leading to significant disability. We will use a mouse model of osteomyelitis in which femurs will be infected with Staphylococcus aureus, the bacterium responsible for the majority of osteomyelitis cases. We have recently used this model to show that bone loss can be prevented by blocking the cytokine RANKL, which drives production of bone resorbing osteoclasts, and that infection potently stimulates RANKL production by a population of stromal fibroblasts that have not been previously described. We also showed that the number of bone forming osteoblasts is dramatically reduced by infection. However, blocking RANKL action is unlikely to be used in the clinic due to the possibility of increasing the amount of dead and infected bone since blocking RANKL completely suppresses osteoclast formation and bone remodeling. If successful, our studies may reveal an approach to specifically block infection-associated osteoclast formation, thereby reducing the likelihood of accumulating dead bone. In addition, our studies may identify ways to restore production of osteoblasts in osteomyelitis and thereby preserve bone without suppressing bone remodeling. This approach also is unlikely to cause accumulation of dead, infected bone. Based on this, we propose the central hypothesis that the profound bone loss in osteomyelitis is due to extraordinarily high RANKL production by a novel infection- associated stromal cell population coupled with simultaneous inhibition of osteoblast differentiation. Further, this inhibition of osteoblast differentiation may be due to diversion of osteoblast progenitors to the production of infection-associated stromal cells. In the first aim we will identify the cells producing RANKL in infected bone and the signaling pathways leading to high RANKL production. We will also determine whether proteolytic processing of RANKL is involved in the pathological bone loss. In the second aim we will determine if infection diverts osteoblast progenitors to an alternative fate, namely, differentiation into the RANKL-producing stromal fibroblasts. For these studies, we will use a novel lineage-tracing mouse model that we have recently created to follow the fate of osteoblast progenitors. We will also determine whether stimulation of osteoblast formation using the anti-sclerostin antibody romosozumab reduces bone loss in infected femurs. Significance and Impact to Veterans Healthcare. Successful completion of these studies may identify approaches to slow or prevent the rapid bone loss that occurs with osteomyelitis and thereby delay the need for amputation. This would provide much needed time for intensive antibiotic therapy to help clear the infection and possibly avoid amputation altogether. Our studies directly address the lack of knowledge regarding the causes of rapid bone loss in osteomyelitis. These studies are also directly relevant to ORD Strategic Priority #2, which is to increase the substantial real-world impact of VA research. Path to translation/implementation. The next steps to move the research along the translational pathway will depend on the outcome of our studies. For example, if we find that stimulating bone formation with romosozumab reduces bone loss but does not inhibit clearance of the infection by antibiotics and the immune system, then clinical trials would be proposed to determine whether this FDA-approved antibody can slow bone loss in osteomyelitis patients. Project Number: 1I01BX007266-01 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: CHARLES O'BRIEN | Institution: CENTRAL ARKANSAS VETERANS HLTHCARE SYS, NORTH LITTLE ROCK, AR | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 ENDB-P (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11190757