Signaling pathways in rheumatoid arthritis: implications for targeted therapy

Abstract

Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.

Fig. 1

General features of rheumatoid arthritis. Rheumatoid arthritis is an incurable autoimmune disease that occurs most frequently in women, usually in the small joints, with systemic complications that ultimately lead to disability

Fig. 2

Risk factors and systemic complications of RA. Genetic and environmental factors are important in inducing RA. While RA mainly affects the joints, it can also influence other organ systems, including the eyes, nerves, skin, kidneys, lungs, liver, heart, and bones

Fig. 3

Normal and rheumatoid arthritis joints. Joint swelling in RA reflects synovial inflammation due to immune activation. The cellular composition of RA synovitis is characterized by the accumulation of innate and adaptive immune cells (e.g., T cells, dendritic cells, B cells, macrophages, and osteoclasts). Pro-inflammatory and bone-destructive factors of the immune response led to the loss of bone or cartilage with synovial thickening, angiogenesis, and muscle wasting

Fig. 4

Cytokine signaling and anti-rheumatic drugs in RA. In the presence of certain environmental or genetic factors, a stepwise progression from activation of innate immunity can be achieved by stimulating DCs, then recruiting and activating T cells, which in turn stimulate B cells, macrophages, synoviocytes, chondrocytes, and osteoclasts to secrete pro-inflammatory and bone-destroying cytokines (i.e., IL-1β, IL-6, TNF-α, and matrix metalloproteinases (MMPs), resulting in bone and cartilage damage accompanied by synovial membranes thickening and angiogenesis, in the synovium and adjacent bone marrow, and the integration of adaptive and innate immune pathways to promote tissue remodeling and damage drives the chronic phase of RA. Clinically, drugs that target inflammatory cytokine signaling are commonly applied

Fig. 5

Main signaling pathways and their inhibitors related to RA. The JAK signaling pathway, Notch signaling pathway, MAPK signaling pathway, Wnt signaling pathway, PI3K signaling pathway, and SYK signaling pathway are the main signaling pathways involved in the process of RA. Related signalings are often the potential targets for drug discovery

Fig. 6

Epigenetic modifications and rheumatoid arthritis. DNA methylation, histone modifications, and-coding RNA mechanisms are often involved in the development of RA