Arthritis is a degenerative disease that affects more than 66 million individuals in the United States alone. The destruction of the extracellular matrix of cartilage and bone is thought to be mediated by excessive proteolytic activity and an imbalance between inflammatory cytokines and their antagonists. The discovery of matrix-degrading enzymes and the inhibitors that antagonize the actions of cytokines is therefore important from both a pathophysiological and a therapeutic standpoint.

In the Liu Lab, our studies have led to the identification of ADAMTS-7 and ADAMTS-12 as two metalloproteinases associated with cartilage destabilization and the pathogenesis of arthritis.

In addition to our investigation into the role of ADAMTS, we have turned our attention to progranulin (PGRN), an autocrine growth factor-like molecule with multiple functions, because it was originally isolated as both a chondrogenic and osteoarthritis-related growth factor in our laboratory. Importantly, we also identified PGRN as a novel binding partner of tumor necrosis factor (TNF) receptors, also known as TNFRs, which are implicated in the regulation of inflammation and autoimmunity.

Armed with this knowledge, we focused on the therapeutic potential of PGRN by isolating the domains of PGRN that interact with TNFRs, which led to the development of an engineered protein called “Atsttrin.”

Our primary focus, accordingly, is to further investigate the roles of PGRN in arthritis and autoimmune diseases, in hopes of using PGRN and its derivatives, particularly Atsttrin, in the development of new interventions for various degenerative and inflammatory conditions.

In our efforts to determine the role of PGRN in lung inflammation, we unexpectedly identified PGRN as a factor involved in Gaucher disease, the most common lysosomal storage disease. Isolation of PGRN as a Gaucher disease modifier provides a foundation for future discoveries relating to this crucial factor in its disease pathogenesis, as well as in uncovering a unique target for developing novel therapies to combat Gaucher disease and probably other lysosomal storage diseases as well.