M. Farooq Rai, Ph.D
Department of Orthopaedics Washington University
BJC - Institute of Health
11th floor - RM 11620
Phone: (314) 286-0955
Dr. Rai is interested in understanding the early molecular mechanisms that orchestrate changes in knee joint after injury and lead to the development of osteoarthritis. He is also interested in developing treatment strategies for this highly prevalent and debilitating joint disease. He has been trained in cellular and molecular biology and has extensive experience in generating intelligent constructs to regulate the expression of therapeutic gene. He has 7+ years of experience in developing and studying mouse models of cartilage repair and osteoarthritis and defining early osteoarthritis in patients using RNA screening techniques to define phenotypes of cartilage, ligament and meniscus after knee injury in collaboration with orthopedic surgeon Dr. Robert Brophy. Working with Dr. Brophy, Dr. Rai is focused on identifying early molecular events in the process of osteoarthritis with the goal of developing treatment options to arrest these early molecular manifestations and prevent late sequelae of the disease.
Cartilage repair in mice. Dr. Rai’s laboratory investigates the basic and translational aspects of musculoskeletal research. The focus is on tissue injury, repair and osteoarthritis. Using a population genetics approach, we have discovered certain mouse lines that have unusual abilities to repair ear and knee cartilage after injury and are protected from developing post-traumatic osteoarthritis. While phenotypic differences have been identified it remains unknown how differential response in healing takes place at cell and gene level. The ongoing work on chondrocytes and stem cells as well as transcriptome profiling of various knee joint tissues in the healer and non-healer mouse lines would unravel cell and transcript level cues as to why some individuals can repair their damaged or loss tissues and are protected from osteoarthritis while others cannot repair their injured tissues and are susceptible to osteoarthritis.
Post-traumatic osteoarthritis in mice and men. As we know that 50+ million Americans are affected by osteoarthritis, 12% of osteoarthritis is due to trauma to knee. Therefore, Dr. Rai’s lab focuses on post-traumatic osteoarthritis in mice and men. The studies on post-traumatic osteoarthritis have been undertaken with the overall goal to underpinning of molecular changes immediately after the injury but before the onset of clinical disease characterized by cartilage fibrillation, synovitis and narrowing of joint space width. This approach of understanding the disease before the clinical manifestations is of paramount significance in translational medicine as one of the main reasons why no effective therapy is available for osteoarthritis is the lack of understanding of the early (molecular) changes in the knee which occur 10-15 years before clinical disease and diagnosis. Currently osteoarthritis is diagnosed at the end stage where no therapy is possible and surgical joint arthroplasty is the only answer. This, if we can move the focus from end-stage disease to early molecular detection, we can better understand the disease process and can identify a window of opportunity for devising new therapeutic candidates as well as new therapeutic targets. To gain mechanistic insights into the tissue injury and osteoarthritis, we have developed surgical (invasive) and mechanical (non-invasive) mouse models of meniscus and ligament injuries.
Post-traumatic osteoarthritis as a function of meniscus injury. Post-traumatic osteoarthritis has an initiating injury or trauma associated with its onset. While osteoarthritis encompasses all knee joint tissues, the focus of research over the past several decades has been on the articular cartilage. Undoubtedly, the work on articular cartilage has advanced our understanding of the liaison between cartilage degeneration and osteoarthritis, but this bias towards cartilage-centric research may hamper a more comprehensive of the impact of osteoarthritis on the joint as a whole. Work on the knee meniscus, central to knee joint congruence as well as other aspects of its physiology, has largely been ignored until recently. While the role of the intact meniscus in osteoarthritis is unclear, meniscus injury certainly plays a vital role in the onset and progression of osteoarthritis and may act as early warning system for prospective osteoarthritis. In contrast to previous research focused on the biomechanics and gross structural and functional aspects of meniscus, we pioneered work studying the molecular biology of the meniscus. This work has led to the identification of transcript level changes in meniscus reflecting the molecular phenotype, in relation to age, obesity, sex, injury pattern, and status of articular cartilage. As these patient-related factors have been implicated in osteoarthritis, their relationship to meniscus injury segues to the interaction of meniscus injury and osteoarthritis. Another significant aspect of our approach is the evidence that the molecular status of the meniscus at injury can potentially predict patients that will develop osteoarthritis. Molecular signatures in articular cartilage and known genetic risk alleles may tell us who will go on to develop osteoarthritis immediately after a meniscus injury has occurred. Our research on molecular profiling of injured meniscus has identified pathways that put older and heavier patients, as well as females, at greater risk for knee osteoarthritis after meniscus injury. While transcriptome profiling in conjunction with osteoarthritis risk-alleles suggests a molecular “pre- osteoarthritis” phenotype in some patients, the ability to predict a population at risk for osteoarthritis can only be assessed by long term clinical follow up studies. These findings outline an emerging paradigm that the metabolic state of the injured meniscus is dependent on several patient-related factors and may be predictive of future disease. These observations may advance our understanding of how this common injury turns the knee in the direction of osteoarthritis.