Liu Lab: Projects

Progranulin: A Novel Growth Factor in Joint Development and Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease that affects more than 46 million people in the United States alone. Since the mechanisms by which OA ensues are largely unknown, there are no therapeutic targets that effectively prevent and treat the disease. However, growth factors, cytokines and matrix-degrading enzymes are strongly implicated in initiating and aggravating OA lesions. Thus, a molecular understanding of interplays among these molecules will provide invaluable information toward the search for novel therapeutic targets for OA. Progranulin (PGRN) was recently isolated as a novel chondrogenic growth factor and an OA-related molecule. It inhibits the catabolic actions of cytokines and cartilage-degrading activities of metalloproteinases. Deletion of the PGRN gene exacerbates, whereas recombinant PGRN prevents, cartilage degradation and joint destruction in various OA models. This project specifically focuses on the role of PGRN in joint biology and in the pathogenesis of OA as well as the molecular events involved. This project may not only benefit our understanding of the molecular mechanisms by which growth factor and cytokine act in concert in chondrocytes and in OA, but may also lead to the development of novel therapeutic intervention strategies for degenerative diseases, including OA.

Progranulin: A Therapeutic Target in Rheumatoid Arthritis and Other Autoimmune Diseases

TNFa has received the greatest attention because of its position at the apex of the pro-inflammatory cytokine cascade, and its dominance in the pathogenesis of inflammation. Anti-TNF therapies have been accepted as the effective approach to treating rheumatoid arthritis (RA) and other autoimmune diseases. In a global screen for the binding proteins of progranulin (PGRN) growth factor, we found that PGRN bound to TNFR1 and TNFR2. Loss of PGRN signaling rendered B6 mice highly susceptible to collagen-induced arthritis (CIA), whereas recombinant PGRN prevented inflammation arthritis in CIA and TNF transgenic mice models. This project focuses on the therapeutic role of PGRN and its derivatives in RA and other autoimmune diseases, including inflammatory bowel disease (Crohn's diseases, Ulcerative Colitis), plaque psoriasis, ankylosing spondylitis, lung inflammation and multiple sclerosis. Successful completion of the proposed research will not only provide new insights into the pathogenesis of RA, but may also lead to the development of novel therapeutic intervention strategies for inflammatory arthritis and other TNFR-mediated pathologies and conditions.

ADAMTS Metalloproteinase in the Musculoskeletal Development and Diseases

The destruction of the extracellular matrix of cartilage and bone is thought to be mediated by excessive proteolytic activity and the imbalance between inflammatory cytokines and their antagonists. The discovery of matrix-degrading enzymes and the inhibitors that antagonize the actions of cytokines are therefore important from both a pathophysiologic and a therapeutic standpoint. Our studies led to the identification of ADAMTS-7 and ADAMTS-12 as two metalloproteinases associated with the cartilage and the pathogenesis of arthritis. These discoveries not only have provided insights into the role of metalloproteinases and their functional interplay in skeletal and joint biology, but also may provide new therapeutic targets to treat chronic degenerative disorders. This project is to determine the roles of ADAMTS metalloproteinases, and to delineate more precisely the pathways in which these molecules participate in developmental biology of joint and bone as well as skeletal diseases, including arthritis and osteoporosis.

Interferon-Inducible Proteins in Immunity, Infection and Inflammation

Interferons (IFNs) are cytokines with multiple biological activities whose actions are realized through numerous INF-inducible molecules. Our studies of interferon-inducible p200 family proteins, with a special focus on p204, revealed that the proteins of this family are important regulators of cell proliferation, differentiation and interferon activity. These studies provide new information concerning the regulation of proliferation, differentiation, and development, promise to lead to greater understanding of the role of interferon in growth and development, and provide a biologic basis for designing therapeutic approaches for a wide range of disorders. Recently, p204/IFI16 was isolated as a cytoplasmic DNA sensor that induces the transcription of genes involved in the innate immune response, including TNFα/β. In addition, it also has the capacity to form an inflammasome within the nucleus and to sense viral DNA in this location. This project is to continue our studies on the physiological and pathological roles of interferon-inducible proteins as well as the cellular and molecular mechanisms involved via the use of human participants, genetically modified mouse models, organ cultures, and in vitro cell systems.