Overview
The Center for Musculoskeletal Disease Research is a Center of Biomedical Research Excellence (COBRE) at UAMS funded by the National Institute of General Medical Sciences (NIGMS). The CMDR is a multidisciplinary center that encompasses a broad area of musculoskeletal research, including osteoporosis, orthopedics, biomechanics, multiple myeloma, and cancer metastases to bone, osteoarthritis, osteomyelitis, and aberrant skeletal development. The long-range goal of the Center is to establish the scientific foundation for sustained excellence in musculoskeletal research in central Arkansas. One important component of this effort is to fund pilot projects as a means of supporting the efforts of musculoskeletal investigators to pursue extramural funding. More information on how the CMDR is structured, our core facilities, and services can be obtained on our website or by contacting the CMDR Director, Dr. Charles O’Brien at caobrien@uams.edu.
Projects
Ryan M. Allen, Ph.D.
Assistant Professor, Physiology & Cell Biology Faculty
Osteomyelitis is an infection of bone and surrounding soft tissue. Bone infections typically arise through one of three primary clinical conditions: 1) osteomyelitis spread from a contiguous source (trauma or surgical contamination), 2) osteomyelitis that is secondary to vascular insufficiency or neuropathy (e.g., diabetic foot ulcers), and 3) acute hematogenous osteomyelitis, which is most common in pediatric patients. Staphylococcus aureus is the most common etiological agent of these infections because it adheres strongly to bone matrix and implanted biomaterials, and because it rapidly forms biofilms that enable persistent colonization. S. aureus also evades host immunity by hiding within host cells (e.g., osteoblasts, osteoclasts), expanding within necrotic tissues that are inaccessible by host immune cells, and secreting a remarkable armament of virulence factors that target the function and viability of host cells. Antibiotic therapy for osteomyelitis is often ineffective due to widespread antibiotic resistance, but treatment of even antibiotic-sensitive strains is often unsuccessful due to limited delivery within biofilms and reduced metabolic rate of S. aureus within the bone microenvironment. Instead, treatment of S. aureus osteomyelitis often requires surgical debridement of infected bone and tissue and long courses of antibiotics. Despite these aggressive and invasive treatment strategies, many patients go on to develop chronic infections, suffer disease-related comorbidities, and/or require amputation. Thus, there is an urgent need for therapeutic innovations that improve infection control and provide effective public health interventions.
The objective of our proposal is to determine whether dietary fats can influence the host response during S. aureus osteomyelitis. S. aureus has a natural weakness to polyunsaturated fatty acids (PUFA), an essential fatty acid that can only be obtained from the diet in humans. We hypothesize that dietary PUFA supplementation will stimulate synthesis and secretion of triglyceride-rich lipoproteins (TRL) that will carry PUFA to sites of infection and act as a natural defense against S. aureus infection. We will test this hypothesis by feeding mice with a low-fat diet or different high-fat diets with combinations of fatty acids found in human diet. For instance, we will use a diet with fat sourced from coconut oil (high saturated fat content) or fish oil (high omega-3 PUFA content) and evaluate the effects of diet on bacterial burden, bone disease, and host immune response. If we observe that diets containing high PUFA content reduce disease burden in mice, we will seek to advance human clinical trials testing prophylactic PUFA supplementation for patients with high risk of staphylococcal osteomyelitis (e.g., patients with type 2 diabetes, bone cancer, orthopedic surgery). The outcomes of our research, thus, have profound translational relevance.