The laboratory of Dr. VB Kraus focuses on Osteoarthritis (OA) research. This laboratory studies the pathogenesis of OA, the most prevalent of all forms of arthritis and a leading cause of disability worldwide. This group works to develop novel tools, in the form of molecular markers, to aid translational research into the diagnosis, prognosis, and effective intervention of the disease. The laboratory has ongoing basic research projects involving human and animal in vivo and in vitro studies. Research areas encompassed by this work include arthritis, aging and resilience, tissue regeneration, and molecular mechanisms. Innovation is a key element in the conduct of the studies by Dr V Kraus as exemplified by her awarded patents.

Biomarker development, validation, qualification and tissue regeneration

A cure for OA remains elusive and its management is largely palliative. The development of effective therapeutics for OA has been hampered by the paucity of robust outcome and monitoring measures. A lack of robust biomarkers for identifying individuals at high risk of progression is in large part responsible for the current lack of disease modifying therapies for OA. We recently identified a proteomic panel of serum biomarkers that predict knee OA progression better than the current “best in class” biomarker for predicting OA progression, namely urinary CTXII(1), and traditional measures used to predict OA progression, such as age, sex, body mass index, and radiographic severity of OA. These studies have involved long-term and productive collaboration with Dr. Yi-Ju Li of the DMPI.

The Kraus lab also developed novel biomarkers based on post-translationally modified proteins to distinguish tissue degeneration from regeneration of tissue and to assess tissue turnover in different joints under different conditions (2, 3, 4, 5). These studies have involved a long-term collaboration with Drs. Art Moseley and Erik Soderblom of the Duke Proteomics Core lab, and Swedish proteomic expert, Dr. Patrik Önnerfjord (6). These novel methodologies have enabled us to identify for the first time, an intrinsic regenerative response to injury in the human lower limb joints that is most highly upregulated in ankle and least in hip cartilages. This intrinsic repair capacity would counteract distal extremity micro and macroinjury and is likely to explain at least in part, the long known inherent ability of ankle joints to resist the development of OA. These studies also have extended to analyses of cartilage and synovium cross-talk revealing that the majority of inflammatory factors in OA stem from the synovium while the cartilage mounts a counter-offensive in the form of growth factor expression that drives an anabolic response(7). This work has been done in collaboration with Drs. Simon Gregory and Ming-Feng Hsueh of the DMPI.

The Kraus lab has also performed extensive novel analyses of extracellular vesicles (EVs) as vehicles of therapeutic cargo and as biomarkers(8,9). These studies have shown that circulating plasma EVs reflect the state of the immune system in humans and mice and are modulated in mice by heterochronic parabiosis in a manner suggesting the ability of EVs to be mediators of improved healing responses of adult parabiosed mice subjected to fracture. This work has been done in collaboration with Drs. Gurpreet Baht and Xin Zhang of the DMPI.

Dr. Kraus has been co-PI with Dr. David Hunter of Australia, of a large international collaborative endeavor (the OARSI/Foundation for NIH Biomarker Initiative), now in phase 2, to pursue FDA and EMA qualification of biochemical and imaging biomarkers as drug development tools for OA (10,11,12,13,14).   The V Kraus laboratory contains repositories of many unique sample sets for future collaborative studies including the DNA and biospecimens from the large multi-family GOGO study (15), Beijing OA Study (16,17), Duke Established Populations for Epidemiologic Studies of the Elderly (Duke-EPESE) cohort(18), and Performance Across the Lifespan Study (PALS)(19), to name a few.

Role of Inflammation in Osteoarthritis

The Kraus lab has been working to understand the pathogenesis of OA. Numerous investigations have focused on the role of innate immunity, including macrophages, in disease progression (20,21,22,23,24,25) and OA as a chronic wound healing response (26). Based on Kraus lab observations, uric acid(27), in addition to other innate immune mediators such as complement and coagulation pathway components(1), are involved in the innate immune response in OA and OA progression of knee OA.

Post-traumatic Osteoarthritis

Current data suggest that a large proportion of severe joint injuries result in post-traumatic osteoarthritis (PTOA); for anterior cruciate ligament rupture, the incidence of OA is as high as 50%. This form of OA affects many young people, starting for many with sports injury as an adolescent. 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 (28,29). The lab has conducted a pilot study of intra-articular IL-1Ra treatment of acute Anterior Cruciate Ligament (ACL) (30) 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 a steering committee member of the Osteoarthritis Clinical Trial Network of the Arthritis Foundation focused on developing infrastructure to accelerate scientific innovations to prevent and treat PTOA. This work has involved 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, done in collaboration with Dr. Brian Soher of the Duke Center for Brain Imaging and Analysis, with leadership by Dr. Xiaojuan Li and of the Cleveland Clinic Foundation. The Kraus lab has also collaborated extensively with the laboratory of Dr. Steve Olson, Orthopaedic Surgeon at Duke University, to investigate 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 (31,32,33,34,35) and Dr Samuel Adams, Orthopaedic Surgeon at Duke University, to develop an improved methodology for radiographically characterizing ankle OA and to investigate risk factors related to PTOA after ankle trauma(36,37,38). 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 (39). For these investigations in PTOA, our team was awarded the Kappa Delta award from the American Academy of Orthopaedic Surgeons and the Orthopaedic Research Society in 2015.

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 (40,41,42,43,44,45) including a definitive chapter of the histological assessment methods most appropriate for this model system (46). We are using this model system to evaluate joint tissue regeneration responses to the anabolic miRNA we discovered to date(47). These studies hold great promise for promoting intrinsic response mechanisms for joint repair and healing after sustained micro and acute microinjury that increase the risk of OA and progressive OA.

News Articles

1. Model to Predict Life Expectancy of Older People
2. Regenerating Damaged Joints
3. Three DMPI faculty members awarded Distinguished Professorships
4. Humans Have Salamander-Like Ability to Regrow Cartilage in Joints
5. OARSI bestows lifetime achievement award to Virginia Kraus
6. Virginia Kraus Elected Member of Association of American Physicians

Supplemental documentation for Daghestani, Pieper, and Kraus article Soluble Macrophage Biomarkers Indicate Inflammatory Phenotypes in Patients with Knee Osteoarthritis. Arthritis Rheumatism. 2015, Dec 29. doi: 10.1002/art.39006. [Epub ahead of print].

Chapters included in Rheumatology, 2-Volume Set, 7th Edition, 2019
by Marc Hochberg, Alan J. Silman, Josef Smolen, Michael Weinblatt, and Michael Weisman.

• Chapter 187: Preclinical and early osteoarthritis
• Chapter 212: Rare osteoarthritis: ochronosis and Kashin-Beck disease

Duke Rheumatology and Immunology 

The Osteoarthritis Research Society International (OARSI)