Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial membrane, leading to cartilage destruction and bone erosion. Due to the complex pathogenesis of RA and the limitations of current therapies, increasing research attention has been directed towards novel strategies targeting fibroblast-like synoviocytes (FLS), which are key cellular components of the hyperplastic pannus. Recent studies have highlighted the pivotal role of FLS in the initiation and progression of RA, driven by their tumour-like transformation and the secretion of pro-inflammatory mediators, including cytokines, chemokines and matrix metalloproteinases. The aggressive phenotype of RA-FLS is marked by excessive proliferation, resistance to apoptosis, and enhanced migratory and invasive capacities. Consequently, FLS-targeted therapies represent a promising avenue for the development of next-generation RA treatments. The efficacy of such strategies – particularly those aimed at modulating FLS signalling pathways – has been demonstrated in both preclinical and clinical settings, underscoring their therapeutic potential. This review provides an updated overview of the pathogenic mechanisms and functional roles of FLS in RA, with a focus on critical signalling pathways under investigation, including Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), Notch and interleukin-1 receptor-associated kinase 4 (IRAK4). In addition, we discuss the emerging understanding of FLS-subset-specific contributions to immunometabolism and explore how computational biology is shaping novel targeted therapeutic strategies. A deeper understanding of the molecular and functional heterogeneity of FLS may pave the way for more effective and precise therapeutic interventions in RA.

Preventing the destruction of articular cartilage has long been a goal in the treatment of arthritic diseases, in which a combination of cytokines and growth factors affect the catabolic state of cells within the joint. Normal tissue turnover can be viewed as a balance between degradation and synthesis of the macromolecules that constitute the extracellular matrix. This process is tightly regulated such that highly degradative proteinases are controlled at several levels, including synthesis and secretion, activation and inhibition. Tissue destruction occurs when proteinase-mediated degradation exceeds synthesis, and this is markedly influenced by cytokines and growth factors that stimulate matrix synthesis as well as the production of proteinases and/or their endogenous inhibitors. This review outlines current knowledge of factors that influence cartilage biology, with particular emphasis on chondrocytes and synovial fibroblasts. Recent findings from the delivery of cytokines to affected tissues are also summarised, and the potential impact these observations might have on new therapies for arthritic diseases is discussed.

We sought to study the effect of synovectomy on the surface morphology of articular cartilages of the rabbit knee using scanning electron microscopy (SEM). Fifteen rabbits were surgically synovectomised and allowed to regenerate their synovia during time intervals ranging from 3 to 44 wk. Cartilage specimens were shaved from 5 distinct articular sectors of synovectomised, contralateral and sham-operated knees and prepared for SEM using tannic acid. Applying structural reinforcement by tannic acid was found to secure the in vivo surface morphology of the cartilages and thus production of surface irregularities during preparation was excluded. The surface morphology of cartilages both from the synovectomised and contralateral joints was found to differ from that of intact healthy rabbits. A ‘chaotic’ nature of the altered cartilaginous morphology persisted as late as 44 wk postsynovectomy. Cartilages from sham-operated joints did not differ detectably from normal cartilages.