Flightless I is a catabolic factor of chondrocytes that promotes hypertrophy and cartilage degeneration in osteoarthritis

Abstract

Summary Synovial macrophages that are activated by cartilage fragments initiate synovitis, a condition that promotes hypertrophic changes in chondrocytes leading to cartilage degeneration in OA. In this study, we analyzed the molecular response of chondrocytes under condition of this type of stimulation to identify a molecular therapeutic target. Stimulated macrophages promoted hypertrophic changes in chondrocytes resulting in production of matrix-degrading enzymes of cartilage. Among the top-upregulated genes, FliI was found to be released from activated chondrocytes and exerted autocrine/paracrine effects on chondrocytes leading to an increase in expression of catabolic and hypertrophic factors. Silencing FliI in stimulated cells significantly reduced expression of catabolic and hypertrophic factors in cocultured chondrocytes. Our further results demonstrated that the FliI-TLR4-ERK1/2 axis is involved in the hypertrophic signaling of chondrocytes and catabolism of cartilage. Our findings provide a new insight into the pathogenesis of OA and identify a potentially new molecular target for diagnostics and therapeutics.

Production and Secretion of Gelsolin by Both Human Macrophage- and Fibroblast-like Synoviocytes and GSN Modulation in the Synovial Fluid of Patients with Various Forms of Arthritis

“…It is conceivable that gelsolin functions in a similar manner. In addition to gelsolin itself, other members of the gelsolin family, such as Flightless I, are also involved in the hyperthrophy and degradation of chondrocytes and thus directly in arthritis itself [46]. Given the many members of the gelsolin family involved, such as scinderin (adseverin) [47] as well, and their seemingly opposing roles in arthritis, further research on this topic is needed to understand the involvement of gelsolin in arthritis.…”

Noncanonical Pyroptosis Triggered by Macrophage‐Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis

“…Additionally, cartilage was fixed using 4% paraformaldehyde (Wako) for 48 hours, decalcified by EDTA solution (Wako) for 2 weeks, and then embedded in paraffin. Sections were stained using Safranin O–fast green staining (Wako), and quantification of stained regions was performed using ImageJ version 1.53t (11).…”

“…Degradation products derived from the extracellular matrix and related molecules act as DAMPs that activate synovial macrophages via pattern-recognition receptors (6)(7)(8)(9). Proinflammatory mediators that are released from inflammatory macrophages initiate cartilage catabolism and activate chondrocytes to produce enzymes that catalyze the degradation of extracellular matrix molecules such as matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS) (10,11). Persistent inflammation and cartilage degeneration cycle results in progressive cartilage destruction and the development of OA.…”

Post-traumatic osteoarthritis: A review of pathogenic mechanisms and novel targets for mitigation

“…Cartilage ECM components such as aggrecan released in increased numbers after chronic or acute trauma to the cartilaginous surface polarize synovial macrophages via NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)/inflammasome mechanism ( Blom et al, 2007 ; Ebata et al, 2021 ). Macrophages respond to aberrant mechanical loading stimuli through transient receptor potential vanilloid type receptors (TRPV) 1 and 4, which stimulate their polarization through the NLRP3/inflammasome mechanism ( Arya et al, 2021 ; Escolano et al, 2021 ; Lv et al, 2021 ; Maruyama et al, 2019 ).…”