Highlights of Strategies Targeting Fibroblasts for Novel Therapies for Rheumatoid Arthritis

Abstract

Synovial fibroblasts of rheumatoid arthritis (RA) play a critical role in perpetuation of chronic inflammation by interaction with immune and inflammatory cells and in cartilage and bone invasion, but current therapies for RA are not directly targeted fibroblasts. Selectively fibroblast targeted therapy has been hampered because of lack of fibroblast specific molecular signature. Recent advancement in technology enabled us to gain insightful information concerning RA synovial fibroblast subpopulations and functions. Exploring fibroblast targeted therapies have been focused on inducing cell death via fibroblast associated proteins; interrupting fibroblast binding to matrix protein; blocking intercellular signaling between fibroblasts and endothelial cells; inhibiting fibroblast proliferation and invasion; promoting cell apoptosis and inducing cellular senescence, and modulating fibroblast glucose metabolism. Translation into clinical studies of these fibroblast targeted strategies is required for evaluation for their clinical application, in particular for combination therapy with current immune component targeted therapies. Here, several strategies of fibroblast targeted therapy are highlighted.

Fibroblast heterogeneity: Keystone of tissue homeostasis and pathology in inflammation and ageing

“…In addition to the epigenetic machinery, strategies that target the imbalanced metabolic pathways in both RA SFs and CAFs have been employed to reduce RA severity and inhibit tumour growth respectively (158,159)). Interestingly, a recent study proposes a new strategy to control fibrosis and hypertrophic scars formation using an anti-glycolytic agent that regulates fibroblasts activity (160).…”

Fibroblast Insights into the Pathogenesis of Ankylosing Spondylitis

“…22 First, similar to rheumatoid arthritis synovial fibroblasts (RASFs) in RA, ASFs can cause certain pathological responses in diseases by regulating factor secretion, coordinating inflammatory responses, regulating tissue homeostasis, and mediating joint remodeling. Currently, fibroblast research in RA is well-established, 23 with key findings in fibroblast subpopulations, fibroblast interactions, 18 and fibroblast-targeted therapies, 24,25 among others. AS and RA are autoimmune diseases with significant differences but certain similarities, especially in inflammation.…”

Glucose as a Potential Key to Fuel Inflammation in Rheumatoid Arthritis

“…This showed the involvement of a broad range of cytokines but not of a single one [ 10 ]. It is suggested that HK is the target of the RASF-specific strategy for the RA-specific glycolysis regulation because HK is highly expressed in the RASF [ 8 , 15 ].…”