Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Rheumatoid Arthritis.

Inês P Perpétuo,Ana Maria Rodrigues,João E Fonseca,Mari Ainola,Helena Canhão,Joana Caetano-Lopes,Raquel Campanilho-Marques,Cristina Ponte

doi:10.1155/2017/2690402

Abstract

Objective. Tumor necrosis factor (TNF) increases circulating osteoclast (OC) precursors numbers by promoting their proliferation and differentiation. The aim of this study was to assess the effect of TNF inhibitors (TNFi) on the differentiation and activity of OC in rheumatoid arthritis (RA) patients. Methods. Seventeen RA patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers, in vitro OC differentiation assays, and qRT-PCR for OC specific genes was performed. Results. After TNFi therapy, patients had reduced RANKL surface expression in B-lymphocytes and the frequency of circulating classical CD14brightCD16− monocytes was decreased. Serum levels of sRANKL, sRANKL/OPG ratio, and CTX-I were reduced in RA patients after TNFi treatment. Moreover, after exposure to TNFi, osteoclast differentiation and activity were decreased, as well as the expression of TRAF6 and cathepsin K. Conclusion. We propose that TNFi arrests bone loss and erosion, through two pathways: direct reduction of osteoclast precursor numbers and inhibition of intracellular signaling pathways acting through TRAF6.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by systemic inflammation, bone erosion, and secondary osteoporosis [1].The immune and skeletal systems have several regulatory factors in common and immune system cells have a profound influence on bone metabolism, in the context of chronic inflammatory diseases
We have shown that RA patients treated with TNF inhibitors (TNFi) have reduced frequency of classic monocytes
We found a decrease in the circulating levels of soluble receptor activator of nuclear factor kappa-B ligand (RANKL) and a reduction in the sRANKL/OPG ratio after TNFi treatment

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by systemic inflammation, bone erosion, and secondary osteoporosis [1].The immune and skeletal systems have several regulatory factors in common and immune system cells have a profound influence on bone metabolism, in the context of chronic inflammatory diseases. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by systemic inflammation, bone erosion, and secondary osteoporosis [1]. TNF, together with other cytokines, acts synergistically with the RANKRANKL system [3, 4], further enhancing osteoclast (OC) differentiation from its circulatory precursors (monocytes) and contributing to bone resorption [2, 5]. It increases the number of circulating OC precursors and the proinflammatory cytokine levels in RA patients. TNF inhibitors (TNFi) have a beneficial effect in delaying radiographic damage in RA patients, even in the absence of clinical improvement, suggesting a specific effect of TNF inhibition, independent of inflammation control [9]

Methods

Results

Conclusion