14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis

Abstract

ObjectivesOsteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA.MethodsBiochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA.ResultsSignalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN’s therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes.ConclusionsThis study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

“…Neurodegenerative disorders are characterized by progressive neuronal loss and deposition of dysfunctional proteins [ 2 ]. To examine the physiological function of PGRN in the CNS, we leveraged PGRN knockout mice ( Grn −/− ) ( Supplementary Figure S1 ) maintained in the laboratory [ 23 , 24 , 25 , 26 ]. The brain tissues from 12 m WT or Grn −/− mice were collected and then used to analyze the maturation of the neurons.…”

Scutellarin Protects Against Mitochondrial Reactive Oxygen Species-Dependent NLRP3 Inflammasome Activation to Attenuate Intervertebral Disc Degeneration

“…TNF-α enhances the expression of ADAMTSs and MMPs, leading to a reduction in ECM synthesis and the exaggeration of ECM degradation, among which MMP-13 and ADAMTS-5 play a critical role in Col-2 and Aggrecan levels ( Fu et al, 2021 ). In this study, primary HNPCs were cultured and stimulated with TNF-α with or without scutellarin treatment.…”

Circulating microRNAs differentiate fast-progressing from slow-progressing and non-progressing knee osteoarthritis in the Osteoarthritis Initiative cohort

“… 31 Members of this family have been explored as biomarkers and mechanistic drivers of rheumatoid arthritis (RA) 32 and OA. 33 Of the seven isoforms, YWHAH and YWHAG were detected in synovial fluid from inflammatory joint disease patients, and YWHAH was elevated in the serum compared with healthy controls. 34 , 35 Furthermore, YWHAH was found to correlate with other biomarkers of RA, and like YWHAE could induce inflammatory factors and signaling pathways linked to joint damage.…”