The laboratory of Dr. V Kraus focuses on Osteoarthritis (OA) research. This laboratory studies the pathogenesis of OA, the most prevalent of all forms of arthritis and the second greatest cause of disability worldwide. This group works to develop novel tools to aid in the diagnosis, prognosis, and effective intervention of the disease. The laboratory has ongoing basic research projects involving in vitro and animal model systems as well as biomedical clinical research and translational medicine trials in OA in humans. Most recently, this research team has engaged in proteomic analysis of joint fluid in knee OA to identify potential new biomarkers of OA progression.
Biomarker development, validation and qualification:
The development of effective therapeutics for OA (OA) has been hampered by the paucity of robust outcome and monitoring measures. The Kraus lab has been developing novel biomarkers based on post-translationally modified proteins to distinguish degeneration from regeneration of tissue and to assess tissue turnover in different joints under different conditions (1, 2, 3, 4). These studies have extended to a collaboration with Drs. Art Moseley and Erik Soderblom of the Duke Proteomics Core lab and Swedish proteomic expert, Dr. Patrik Onnerfjord (5). These studies have also extended to a collaboration with researchers at Academia Sinica in Taiwan to look at cartilage and site matched bone with a novel sampling method amenable to isolating high quality tissue for genomic studies (6,7). These studies have extended to evaluation of epigenetic factors regulating OA pathogenesis in collaboration with Drs. Simon Gregory and Beth Hauser of the DMPI. Dr. Kraus has been co-PI with Dr. David Hunter of Australia, of a large endeavor (the OARSI/Foundation for NIH Biomarker Initiative) to use samples and data from the NIH funded OA Initiative to pursue FDA and EMA qualification of biochemical and imaging biomarkers for OA (8). This has included critical work with longtime collaborator Dr. Joanne Jordan of the University of Chapel Hill, NC and Dr. David Hargrove of LabCorp to establish reference ranges for biochemical markers in stringently phenotyped non-OA healthy subjects. The laboratory contains repositories of many unique sample sets for future collaborative studies including the DNA and biospecimens from the large multi-family GOGO study (9), samples from the Doxycycline and longitudinal studies of Dr. Brandt (10), and the Beijing OA Study (11,12), to name a few.
Role of Inflammation in Osteoarthritis:
The Kraus lab has been working to understand the pathogenesis of OA. Recent investigations have focused on the role of innate immunity and macrophages in the disease progression (13,14,15,16) and OA as a chronic wound healing response (17). Based on the Kraus lab observation that uric acid is involved in the innate immune response in OA and OA progression of the knee, a collaborative randomized placebo controlled clinical trial is ongoing of colchicine for knee OA with Dr. Katy Leung at Duke NUS and Singapore General Hospital in Singapore.
Current data suggest that a large proportion of severe joint injuries result in post-traumatic osteoarthritis (PTOA). The time to onset based on radiographic criteria can range from 10-20 years, but may be accelerated considerably in populations experiencing extreme injuries in combination with occupational stresses, such as the military, in whom PTOA may develop in as little as 2-3 years after traumatic injury. The Kraus lab is interested in developing an understanding of the early changes in joint metabolism associated with severe joint injury and through these studies, to understand and test effective means of early intervention and prevention of PTOA (18,19). The lab has conducted a pilot study of intra-articular IL-1Ra treatment of acute Anterior Cruciate Ligament (ACL) (20) that showed great promise. This has been followed by collaborations with Sports Medicine Orthopaedists, in particular Drs. Christian Lattermann and Kurt Spindler, to expand and refine early therapeutic interventions for ACL and joint trauma. To this end, Dr. Kraus also serves as an advisor to the Arthritis Foundation funded Anterior Cruciate Ligament (ACL) initiative focused on validating T1rho MRI for early monitoring of joint abnormalities after severe acute ACL tears with the goal of establishing outcomes for clinical trials in acute joint trauma. The Kraus lab collaborates with the laboratories of Dr. Steve Olson and Dr. Farshid Guilak in investigations of the natural history, biomarkers and interventions in rodent models of acute trauma (fracture) and the impact of diet and mouse strain on severity of PTOA (21,22,23,24,25). Investigations in this model system have been greatly facilitated by the development of a method in the Kraus lab for collecting synovial fluid from the mouse knee (26). Collaboration with the Guilak laboratory has shown that intra-articular delivery of purified mesenchymal stem cells from C57BL/6 or MRL/MpJ superhealer mice prevents post-traumatic arthritis (27).
Animal models of Osteoarthritis:
The Kraus lab is expert in the spontaneous knee OA model in guinea pigs and has published widely in this area (28,29,30,31,32,33) including a definitive chapter of the histological assessment methods most appropriate for this model system (34). In collaboration with the laboratory of Dr. Lori Setton, the lab has also investigated other animal models including NF-kappaB activity, by in vivo luminescent imaging, and serum cytokine levels and their association with pain sensitivities in a rodent model of OA (35).