Resistin Enhances VCAM-1 Expression and Monocyte Adhesion in Human Osteoarthritis Synovial Fibroblasts by Inhibiting MiR-381 Expression through the PKC, p38, and JNK Signaling Pathways

Abstract

The development of osteoarthritis (OA) is characterized by synovial inflammation and the upregulation of vascular cell adhesion molecule type 1 (VCAM-1) in human osteoarthritis synovial fibroblasts (OASFs). This increase in VCAM-1 expression promotes monocyte adhesion to OASFs. The adipokine resistin is known to promote the release of inflammatory cytokines during OA progression. In this study, we identified significantly higher levels of resistin and CD68 (a monocyte surface marker) expression in human OA tissue compared with in healthy control tissue. We also found that resistin enhances VCAM-1 expression in human OASFs and facilitates the adhesion of monocytes to OASFs. These effects were attenuated by inhibitors of PKCα, p38, and JNK; their respective siRNAs; and by a microRNA-381 (miR-381) mimic. In our anterior cruciate ligament transection (ACLT) rat model of OA, the inhibition of resistin activity prevented ACLT-induced damage to the OA rat cartilage and pathological changes in resistin and monocyte expression. We also found that resistin affects VCAM-1 expression and monocyte adhesion in human OASFs by inhibiting miR-381 synthesis via the PKCα, p38, and JNK signaling pathways. Our clarification of the crucial role played by resistin in the pathogenesis of OA may lead to more effective therapy that reduces OA inflammation.

Resistin enhances IL‐1β and TNF‐α expression in human osteoarthritis synovial fibroblasts by inhibiting miR‐149 expression via the MEK and ERK pathways

“…Leptin augments levels of IL‐6 and IL‐8 in human synovial fibroblasts 34,35 . Resistin has been shown to increase angiogenesis and monocyte infiltration during arthritis progression 21,36 . However, it is unclear as to what role resistin plays in inflammatory cytokine production during OA disease.…”

“…We have previously reported that in male Sprague‐Dawley (SD) rats with ACLT‐induced OA, blocking resistin activity ameliorated disease severity by preventing ACLT‐induced effects on subchondral bone architecture and histological changes in resistin and monocyte expression 21 . Of the wide variety of animal models of that are available for studying the pathogenesis of OA, none can be fully extrapolated to the human condition of OA; the data suggest that different models relate to particular subtypes of OA, with distinct molecular mechanisms in joint structural damage and pain that depend on how OA is induced 37 .…”

“…For this investigation into the inter‐relationships between resistin and pro‐inflammatory mediators IL‐1β and TNF‐α during OA pathogenesis, we selected the ACLT OA model as being the most appropriate surgical OA animal model for revealing resistin‐induced molecular changes in the cartilage, synovial tissue, and subchondral bone, all of which can be studied within a short timeframe, as illustrated in our previous study 21,40 . It is well recognized that OA disease progression is closely associated with progressive destruction of articular cartilage, subchondral bone remodeling and inflammatory changes in the synovial membrane although the etiology and pathogenesis of OA is less clear 41 .…”

“…Male Sprague‐Dawley (SD) rats (8 weeks old, weighing 300‐350 g) were bought from the National Laboratory Animal Center in Taiwan and maintained under conditions in accordance with the Guidelines of the Animal Care Committee of China Medical University, Taichung, Taiwan. The anterior cruciate transection (ACLT) rat model induced OA 21,22 . In brief, the right hind knee was prepared in a surgically sterile fashion.…”

Resistin, a Novel Host Defense Peptide of Innate Immunity

“…For instance, resistin up-regulates the expression of chemokines (i.e., CCL2, CCL3, CCL4, CCL5, CXCL1, and CXCL2) via transcription factors NF-kB and C/EBPb in human articular chondrocytes (100). It enhances VCAM-1 expression and monocyte adhesion through the PKC, p38, and JNK signaling pathways in human osteoarthritis synovial fibroblasts (103). In endothelial cells, resistin up-regulates ICAM-1, VCAM-1, fractalkine, and MCP-1 via TLR4, JNK/p38, AP-1, and NF-kB dependent pathways or by Gi/o signaling pathway (104)(105)(106)(107)(108).…”