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

Wenyu Fu¹, Aubryanna Hettinghouse¹, Yujianan Chen¹

¹Department of Orthopaedic Surgery, NYU Grossman School of Medicine, New York, New York, USA.

Annals of the Rheumatic Diseases

|July 6, 2021

Abstract

Objectives:

Osteoarthritis (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.

Methods:

Biochemical 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.

Results:

Signalling 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.

Conclusions:

This 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.

Insights

This study reveals 14-3-3 epsilon as a key player in TNFR2 signaling, crucial for chondrocyte health and osteoarthritis protection. Its deficiency worsens osteoarthritis, highlighting a new therapeutic pathway.

Area of Science:

Cell Biology
Molecular Biology
Immunology

Background:

Osteoarthritis (OA) is a prevalent joint disease with poorly understood mechanisms, hindering therapeutic development.
Tumor Necrosis Factor (TNF) signaling is implicated in OA pathogenesis, with TNFR1 promoting inflammation and TNFR2 showing protective roles.
Understanding TNFR2 signaling in chondrocytes is critical for developing novel OA treatments.

Purpose of the Study:

To investigate the role of TNFR2 signaling in chondrocytes and its involvement in osteoarthritis.
To identify intracellular cofactors of TNFR2 and elucidate downstream signaling pathways in OA.
To explore the therapeutic potential of targeting the TNFR2 pathway in OA.

Main Methods:

Biochemical copurification and proteomics to identify TNFR2 cofactors.
Bulk and single-cell RNA sequencing to analyze 14-3-3 epsilon expression in human cartilage.
Cell-based assays and genetically modified mouse models (surgical and naturally occurring OA) to assess pathway function.

Main Results:

14-3-3 epsilon was identified as an intracellular component of TNFR2 complexes, induced by progranulin (PGRN).
14-3-3 epsilon expression was downregulated in OA cartilage and its deficiency exacerbated OA.
PGRN's protective effects against OA were dependent on 14-3-3 epsilon, which regulates chondrocyte metabolism via ERK/Elk-1 activation and NF-κB suppression.

Conclusions:

14-3-3 epsilon is an inducible component of the TNFR2 receptor complex in chondrocytes, activated by PGRN.
A novel TNFR2 pathway involving PGRN and 14-3-3 epsilon has been identified in osteoarthritis pathogenesis.
This pathway represents a potential therapeutic target for osteoarthritis treatment.

Read full analysis

Keywords:

Chondrocytes Inflammation Osteoarthritis

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