A Novel Regulatory Role of TRAPPC9 in Osteoarthritis
Authors: Hussein Nazar , Safadi Fayez 
Published: June 2021

INTRODUCTION

Trafficking Protein Particle Complex 9 (TRAPPC9) is a major subunit of TRAPPII Complex. TRAPPC9 is implicated in endoplasmic to Golgi trafficking pathway and intra Golgi trafficking in yeast cells. TRAPPC9 has been reported to bind IKKb and NIK where it plays a role in NFkB signaling. Hence, plays a role in different cell types differentiation and function. In osteoarthritis, inflammation mediated by the NFkB signaling plays a role in the pathogenesis on the disease. There are two distinct pathways, which can activate the NF‐kB signaling cascades. The first one termed the canonical or the classical pathway, activation of IKKα/IKKβ/IKKβ‐NEMO complex will activate this pathway. On the other hand, the non‐canonical or the alternative pathway, activation relies on NF‐kB‐inducing kinase (NIK) signaling. Our data showed that TRAPPC9 binds IKKβ and NIK in chondrocytes. We believe such interaction could lead to a potential regulatory role of TRAPPC9 during NF‐kB signaling cascades given that the role of TRAPPC9 in OA has not been studied yet.

METHODS

In this study, we used human chondrocytes and primary mouse chondrocyte cell culture, immunofluorescence, and retroviral transfection techniques.

RESULTS

To explore the role of TRAPPC9 in OA, first, we assessed the expression of TRAPPC9 (mRNA and protein) levels in primary human chondrocytes treated with ILb to resemble chondrocytes within OA knee and found that TRAPPC9 expression is decreased in IL‐1β‐treated chondrocytes compared to controls. Next, we determined whether modulation of TRAPPC9 expression alters the inflammatory markers induced by IL1b that are regulated by NF‐kB signaling pathways. Human chondrocytes were transfected with either TRAPPC9 overexpression plasmid or control plasmid. Gene expression for metalloproteinases (what else a part of MMP) was measured and our data showed that TRAPPC9 overexpression induces inflammation by increasing the gene expression of MMPs‐1,3,9,13, and Interlukin‐6 (IL‐6).

CONCLUSION

We showed that TRAPPC9 binds/interacts with NIK and IKKb in chondrocytes. Also, we were able to show that TRAPPC9 expression is decreased in inflammatory conditions. In addition, our data showed that modulating TRAPPC9 expression prior to IL‐1β induction leads to elevate inflammatory conditions in chondrocytes. Studies are underway to determine the effects of modulating TRAPPC9 using genetic and pharmacologic approaches on osteoarthritis development and identifying the mechanism(s) by which inflammation in chondrocytes mediated by TRAPPC9, NIK, and IKKb interactions. Collectively, these studies are the first to report a novel role for TRAPPC9 in osteoarthritis.

SIGNIFICANCE/CLINICAL RELEVANCE

Understanding the role of TRAPPC9 in osteoarthritis are not reported previously. It is important to investigate whether TRAPPC9, NIK and IKKb interaction mediates inflammation in chondrocytes by modulating the NF‐kB signaling pathways thereby, suggesting new therapeutics for osteoarthritis disease.

Support or Funding Information

Kent State University, School of Biomedical Sciences. Ohio Physiological Society (Peter K Lauf Travel Award).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.