CPT1A-Mediated Fatty Acid Oxidation Promotes Precursor Osteoclast Fusion in Rheumatoid Arthritis

Zhaoyang Huang,Lan Shao,Zhongyang Zhou,Xinyao Zhang,Jiawen Han,Liu Yang,Hongxia Wang,Zhao Wang,Haiqi Chen,Rong Luo

doi:10.3389/fimmu.2022.838664

Abstract

The overproduction of osteoclasts, leading to bone destruction in patients with rheumatoid arthritis (RA), is well established. However, little is known about the metabolic dysfunction of osteoclast precursors (OCPs) in RA. Herein, we show that increasing fatty acid oxidation (FAO) induces OCP fusion. Carnitine palmitoyltransferase IA (CPT1A), which is important for carnitine transportation and is involved in FAO in the mitochondria, is upregulated in RA patients. This metabolic change further increases the expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) by enhancing the binding of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) to the promoters of CLTA and CLTC. This drives clathrin-dependent endocytosis pathway, which attenuates fusion receptors in the cellular membrane and contributes to increased podosome structure formation. This study reveals a new mechanism through which FAO metabolism participates in joint destruction in RA and provides a novel therapeutic direction for the development of drugs against bone destruction in patients with RA.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by progressive destruction of joint cartilage and bone [1]
To study alterations in the lipid metabolic pathway of Osteoclast Precursor (OCP) in RA, the lipidome of peripheral CD14+ monocytes isolated from RA patients and healthy controls (HCs) was comprehensively examined by liquid chromatography coupled with dynamic quantitative mass spectrometry
To further characterize the metabolic state of lipids in RA monocytes, CD14+ monocytes from RA patients and agematched HCs were subjected to Nile red staining to examine the accumulation of intracellular lipid droplets

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by progressive destruction of joint cartilage and bone [1]. Osteoclasts are multinucleated cells that play a critical role in the pathological arthritic bone erosion in patients with RA [2]. They can be formed via cell– cell fusion of circulating mononuclear precursor cells, which are derived from pluripotent hematopoietic stem cells. Recent studies suggested that arthritis-associated OCPs in the pannus originate from circulating blood monocytes but not from locally resident macrophages. Peripheral blood monocytes isolated from patients with RA have enhanced osteoclast genesis capability compared with that from healthy controls (HCs) [5, 6], suggesting that circulating OCPs (monocytes) play a vital role in bone erosion in RA

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