RGS12, a Novel Inflammatory Mediator for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most severe chronic joint disease that causes irreversible joint damage and significant disability. RA is a growing burden among military members, greatly impacting the ability of military Veterans and active-duty members to perform their duties and limiting the quality of life. RA is characterized by synovial inflammation, cartilage and bone destruction accompanying with cardiovascular, pulmonary, psychological, and skeletal disorders. RA has an incidence of about 1%, with an apparent increase from south to north, and from rural to urban areas. Some Native American populations have a very high prevalence. It strikes two to three times more women than men. Although the disease usually first appears during middle age, it often occurs in young adult years in military Veterans and leads to complete joint destruction if the disease remains inadequately treated.

Regulator of G-protein signaling (RGS) proteins play important roles in immune responses. Therefore, RGS proteins may become important and new drug targets for the treatment of immune and inflammatory diseases. RGS12 was first found as the largest protein in the RGS family, which contains multiple domain protein structures and is involved in regulating multiple inflammatory-associated signaling pathways, including G protein-coupled receptors (GPCRs). GPCRs play a critical role in RA pathogenesis. Notably, RGS12 was recently reported to respond to infliximab (anti-TNF therapy) in RA synovial fluid macrophages in RA patients. However, the function and mechanism of RGS12 involved in RA development and progression have not yet been uncovered. We recently found that RGS12 is a new and important inflammatory regulator. We found that RGS12 plays essential roles in bone resorption. Additionally, RGS12 protein significantly increased in synovial fibroblasts (SFs) and macrophages of RA patients and in a mouse RA model. Moreover, loss of RGS12 in macrophages reduced RA incidence. Taken together, evidence strongly supports that RGS12 is a potential new drug target for RA. Therefore, the goal of this project is to characterize the role of RGS12 and to understand the underlying mechanisms by which RGS12 regulates inflammation and bone erosion in RA, and further test whether targeted knockdown of RGS12 using a novel siRNA lipid nanoparticle platform can effectively attenuate RA in the preclinical phase using CAIA mouse model, which well fits the FY20 PRMRP Rheumatoid Arthritis Topic Area.

This proposal will use the new genetic models and targeted nanotechnology to characterize RGS12 as a novel key regulator and potential the drug target for RA. Currently, there is no specific cure for RA. Although clinical studies indicate that the current standard care with early therapy of disease-modifying antirheumatic drugs (DMARDs), e.g., biological DMARD like anti-TNF mAb (infliximab) or non-biological like methotrexate, sulfasalazine, and hydrocychloroquine, have a certain level of improvement for treatment of RA, these agents can lead to generalized suppression of multiple physiologic functions. Hence, identifying new factors that control inflammation and bone erosion especially for RA is urgent and has significant impact. To date, no single therapeutic agent has been shown to effectively inhibit RA and bone erosion. Our findings are expected to reveal new mechanism that RGS12 acts as an inflammatory factor and explore therapeutic potential of targeting RGS12 and demonstrate that inhibition of RGS12 may represent an attractive new or complementary therapeutic approach to suppressing inflammatory and bone resorption in vivo for RA patients. Most importantly, development of novel RGS12 siRNA targeting lipid nanoparticle system for inhibition of inflammation has translational significance not only for RA, but also for periodontitis caused bone loss, aging, and diabetic osteoporosis and other inflammatory-associated diseases.