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 by visiting our website (http://cmdr.uams.edu/) or by contacting the CMDR Director, Dr. Charles O’Brien at caobrien@uams.edu.

Year 1

Melda Onal, Ph.D., Assistant Professor, COM Physiology and Biophysics

Title of the project: “Role of Chaperone Mediated Autophagy in Osteoblast Lineage Cells of the Bone”

Aging is a major risk factors for osteoporosis. Decline in proteostasis is a hallmark of aging and a decline in CMA has been shown to contribute to age related pathologies in some tissues. Thus, understanding physiological role of CMA, its status in and contribution to age-related bone loss can help us identify new therapeutics. Aim 1. Determine whether CMA is induced and utilized as a stress response mechanism in osteoblast or osteocyte cell lines. Aim 2. Perform in vivo loss of function studies to impair CMA and assess the physiological role of CMA in young mice under physiological conditions.

Erin Mannen, Ph.D., Assistant Professor, COM Orthopaedic Surgery

Title of the project: “Biomechanics of non-surgically treated infants with developmental hip dysplasia”

This study aimed to produce (1) a DDH biomechanical dataset both before and after successful treatment to compare to previously collected healthy controls, (2) quantifiable biomechanical measurements of DDH improvement due to the Pavlik harness to compare with currently-used clinical measures, and (3) a novel dataset on DDH patients that can be utilized by researchers to explore improved DDH treatment methods.

Year 2

Ha neui Kim, Ph.D., Assistant Professor, Endocrinology and Metabolism

Title of the project: “Role of Mitochondrial Deacetylase Sirt3 in Skeletal Homeostasis”

The aims of the work proposed in this application is to identify the means by which mitochondrial deacetylase Sirt3 regulates skeletal homeostasis. This will be accomplished by studying
mitochondrial function of the bone cells. Knowledge gained with these studies may prove useful for the development of therapies that can treat osteoporosis. Aim 1 will examine the role of Sirt3 in
skeletal homeostasis by determining the bone phenotype of Sirt3 KO mice at different ages. Aim 2. will investigate whether Sirt3 controls mitochondrial function in primary osteoclast
progenitors as well as in osteoblast progenitors (Aim 2).

Simon Mears, M.D., Professor, COM Orthopaedics Surgery

Title of the project: “Biomechanical Quantification of Flexion Instability after Total Knee Arthroplasty”

Aim 1. To empirically quantify the amount of tibio-femoral translation during clinical examination of patients diagnosed with flexion instability following TKA and compare with the subjective measurement determined by examining surgeons. Aim 2. To quantify inter- and intra-tester variability in examination technique, including knee angle and force application. Aim 3. Correlate the flexion instability grading with functionality and strength.

Year 3

Elisabeth Ferreira, Ph.D.,  Assistant Professor, Endocrinology and Metabolism

Title of the project: “Exploiting the Activity of SYNS GDF5 Variants for the Repair of Large Bone Defects”

More than two million bone grafting procedures are performed every year to manage problematic bone defects. Yet, current treatment strategies cannot ensure healing. The long term goal of this project work is to identify novel therapeutic molecules that more efficiently direct bone healing, preventing nonunion and the serious consequences of this outcome. Aim 1, will use lentiviral vectors to drive overexpression of three GDF5 variants by human and rat bone marrow-derived mesenchymal stem cells (MSCs). Aim 2, will test whether local delivery of these GDF5 variants improves healing of rat critical-sized defects.

Roy Morello, Ph.D., Associate Professor, Physiology and Biophysics

Title of the project: “The role of the small GTPase Rab33b in the skeleton”

The goal of this pilot project is to characterize the functional role of the small GTP-binding protein Rab33b, a regulator of intracellular membrane trafficking, in the skeleton. Pathogenic variants in RAB33B cause Smith-McCort (SMC) dysplasia in humans and we have now generated a mouse model of the disease in which to establish the cellular defects that underlie the pathogenic processes.