Atsttrin Promotes Cartilage Repair Primarily Through TNFR2-Akt Pathway

Abstract

Background: Cartilage defects account for substantial economic and humanistic burdens and pose a significant clinical problem. The efficacy of clinical approaches to cartilage repair is often inadequate, in part, owing to the restricted proliferative capacity of chondrocytes. Molecules have the capacity to promote the differentiation of multipotent mesenchymal stem cells into chondrocytes and may also gain the ability to repair the damaged cartilage.Objective: This study aimed to investigate the role of Atsttrin (progranulin-derived engineered protein) in cartilage repair as well as the signaling pathway involved.Methods: Primary and mesenchymal stem cell lines were used for the micromass culture. A murine cartilage defect model was used to determine the role of Atsttrin in cartilage repair in vivo. Real-time polymerase chain reaction and Western blot analysis were used to monitor the effect of Atsttrin on the transcriptional and protein levels, respectively, of key anabolic and catabolic signaling molecules.Results: Atsttrin stimulated chondrogenesis in vitro and accelerated cartilage repair in vivo. In addition, Atsttrin-mediated cartilage repair occurred primarily through tumor necrosis factor receptor 2-initiated Akt signaling and downstream JunB transcription factor. Conclusion:Atsttrin might serve as a promising therapeutic modality for cartilage regeneration.

Fexofenadine Protects Against Intervertebral Disc Degeneration Through TNF Signaling

“…At the same time, the inflammatory response mediated by immune cells was enhanced in the degenerated IVD, which led to the decrease of the number of NP cells and the deterioration of the IVD microenvironment ( Zhao et al, 2020 ; Lyu et al, 2021 ). TNF-α is at the top of the inflammatory cascade and plays an important role in the progression of IVD degeneration ( Croft et al, 2013 ; Wei et al, 2020a ). TNF-α is a powerful inflammatory factor that is positively correlated with the degree of IVD degeneration ( Risbud and Shapiro, 2014 ; Zhang et al, 2018 ; Yang et al, 2020 ).…”

“…*p < 0.05 and **p < 0.01 vs. control group. (Croft et al, 2013;Wei et al, 2020a). TNF-α is a powerful inflammatory factor that is positively correlated with the degree of IVD degeneration (Risbud and Shapiro, 2014;Zhang et al, 2018;Yang et al, 2020).…”

“…Tumor necrosis factor-α (TNF-α) is one of the molecules in the TNF family ( Croft et al, 2013 ; Wei et al, 2020a ). TNF-α is regarded as the most powerful pro-inflammatory cytokine owing to the top position of the inflammatory cascade reaction ( Tang et al, 2011 ; Liu and Bosch, 2012 ; Wei et al, 2018 ).…”

Progranulin is essential for bone homeostasis and immunology

“…47 Articular cartilage defects in the femoral trochlea of mice have confirmed the protective role of TNFR2 in PGRN-mediated cartilage repair. 32,48 Atsttrin, an engineered protein composed of three TNFR-binding fragments of PGRN, has exhibited therapeutic effects on multiple murine models of inflammatory arthritis. Atsttrin reduced articular cartilage destruction and serum levels of COMP degradative fragments in a Pgrn-KO DMM mouse model.…”

“…49 Mechanistically, Atsttrin promotes chondrogenesis by activating the TNFR2/Akt signaling pathway; subsequently, the downstream transcription factor JunB is activated in a cascade reaction in vitro. 48 Atsttrin-induced collagen anabolism is dependent on the activation of Akt-ERK1/2 signaling via TNFR2. 49 Atsttrin and PGRN disrupt the interaction between TNF-α and TNFR1, antagonizing TNF-α-mediated activation of the nuclear factor kappa-B (NF-κB), β-catenin, and MAPK signaling pathways to delay OA progression.…”