FABP4 knockdown suppresses inflammation, apoptosis and extracellular matrix degradation in IL-1β-induced chondrocytes by activating PPARγ to regulate the NF-κB signaling pathway

Abstract

Osteoarthritis (OA) is a common degenerative disease that can lead to severe joint pain and loss of function, seriously threatening the health and normal life of patients. At present, the pathogenesis of OA remains to be clarified. Recent studies have shown that fatty acid-binding protein 4 (FABP4) is increased in the plasma and synovial fluid of patients with OA. However, the effect of FABP4 on OA is unclear. The present study established IL-1β-induced ATDC5 cells with FABP4 knockdown. Next, cell viability was detected with Cell Counting Kit-8 assay. The content of inflammatory factors, prostaglandin E2 and glycosaminoglycan (GAG) was detected via ELISA. The levels of reactive oxygen species (ROS) and superoxide dismutase (SOD) in cells were detected by using ROS and SOD kits, respectively. TUNEL staining was used to detect the apoptosis level. Western blotting was used to detect the expression levels of proteins. The results revealed that FABP4 was upregulated in IL-1β-induced ATDC5 cells. Knockdown of FABP4 increased cell viability, reduced inflammatory damage, oxidative stress and apoptosis in IL-1β-induced ATDC5 cells. Following FABP4 knockdown, the expression of matrix metalloproteinases (MMP3, MMP9 and MMP13) of IL-1β-induced ATDC5 cells was reduced, and the expression of GAG was promoted. FABP4 knockdown also inhibited the expression of NF-κB p65 and enhanced peroxisome proliferator-activated receptor (PPAR)γ expression. However, the presence of PPARγ inhibitor blocked the aforementioned effects of FABP4 on IL-1β-induced ATDC5 cells. In conclusion, FABP4 knockdown suppressed the inflammation, oxidative stress, apoptosis and extracellular matrix degradation of IL-1β-induced chondrocytes by activating PPARγ to inhibit the NF-κB signaling pathway.

FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis

“…Interestingly, the upregulation of FABP4 was also observed in the articular cartilage of RA mice. Since a previous study showed that IL-1β could stimulate the expression of FABP4 in ATDC5 cells (a chondrogenic cell line), 50 we hypothesized that FABP4 upregulation in RA chondrocytes was induced by excessive proinflammatory factors (IL-1β, IL-6 and TNF-α) derived from synovial M1 macrophages, FLSs and ECs. These data demonstrated that FABP4 secretion by synovial macrophages exacerbated cartilage degeneration by disrupting chondrocyte homeostasis through activation of the NF-κB pathway in RA.…”

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

“…Therefore, FABP4 produced in epicardial/perivascular fat and macrophages within the atherosclerotic lesion upregulates inflammation-related pathways, leading to the development of coronary atherosclerosis [ 14 ]. FABP4 also increases inflammatory cytokines and mediates apoptosis in a variety of cell types [ 15 , 27 ]. The regulation of inflammation and apoptosis seems to be strongly related since FABP4 silencing protects from cardiomyocyte or chondrocyte apoptosis via the master regulator of the inflammation nuclear factor-κB (NF-κB) pathway [ 15 , 27 ].…”

“…FABP4 also increases inflammatory cytokines and mediates apoptosis in a variety of cell types [ 15 , 27 ]. The regulation of inflammation and apoptosis seems to be strongly related since FABP4 silencing protects from cardiomyocyte or chondrocyte apoptosis via the master regulator of the inflammation nuclear factor-κB (NF-κB) pathway [ 15 , 27 ]. Conversely, the downregulation of FABP4 using its specific inhibitor BMS309403 can suppress inflammation and/or apoptosis in pathological settings including acute lung injury, acute kidney injury, or diabetic nephropathy [ 27 , 28 , 29 ].…”

“…Of special interest, ectopic expression of FABP4 in atherosclerotic plaques is due to its excessive production by macrophages that infiltrates within the lesion, being associated with greater local inflammation or plaque vulnerability [ 13 ]. In vitro experiments have shown that the local secretion of FABP4 by epicardial/perivascular fat and macrophages within the atherosclerotic lesion can have paracrine/autocrine effects, upregulating vascular inflammation, or impairing endothelial function, which contributes to the progression of atherosclerotic damage [ 14 ] FABP4 has also been implicated in the modulation of apoptosis in different cell types through the nuclear factor-κB (NF-κB) pathway [ 14 , 15 , 16 ]. Pharmacological blockade of FABP4 with small molecule inhibitors such as BMS309403 have shown to be an effective therapeutic strategy against insulin resistance, diabetes mellitus, and atherosclerosis by suppressing the associated inflammatory and apoptotic processes [ 17 ].…”

A Novel Hypoxia Related Marker in Blood Link to Aid Diagnosis and Therapy in Osteoarthritis

“…NF-κB is regarded as a transcriptional factor that is activated by several pro-inflammatory cytokines. It is closely related to inflammation, apoptosis, oxidative stress, and the extracellular matrix degradation of chondrocytes [ 39 ]. The ubiquitin–proteasome pathway is a major proteolytic pathway.…”