Research Progress--Institute of Zoology Chinese Academy of Sciences

Rheumatoid arthritis (RA) is a common autoimmune disease with a prevalence of about 1% worldwide. RA is characterized by chronic inflammation and high levels of destructive mediators in the synovium, which leads to cartilage and bone destruction. HTRA1 is a secreted serine protease, which acts as both molecular chaperone and proteolytic enzyme. HTRA1 directly promotes the degradation of collogen and some other proteins in cartilage, and inhibits TGF-β

signaling pathway, which is important for the generation of collogen and proteoglycans. Additionally, HTRA1 also sitimulates fibroblasts to secrete matrix metalloproteinase (MMPs), which lead to bone damage. The correlationship between HTRA1 and the occurrence and development of arthritis in clinics has been recognized. However, the micro-environmental extracellular factors and intracellular upstream events that regulate HTRA1 expression in mammalian cells are unknown. Dr. Yong Zhao’s group recently found that toll-like receptor 4 (TLR4) ligands LPS and tenascin-C (TNC) strongly induced HTRA1 expression, whereas IFN-γ inhibited HTRA1 expression in mouse fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the antagonistic effect of LPS and IFN-γ on HTRA1 expression was evidenced in collagen-induced arthritis mouse models and in human synovial cells. Mechanistically, TLR4 ligands and IFN-γ controlled HTRA1 expression through activation of the classical NF-κB and p38MAPK-STAT1 pathway, respectively. This study offers new insights into HTRA1 expression and may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer.