Tumor Necrosis Factor-α Increases Circulating Osteoclast Precursor Numbers by Promoting Their Proliferation and Differentiation in the Bone Marrow through Up-regulation of c-Fms Expression

Qian Zhang,Peter Keng,Brendan F. Boyce,Lianping Xing,Edward M. Schwarz,Zhenqiang Yao,Arnaldo Arbini,Ping Li

doi:10.1074/jbc.m512624200

Qian Zhang, Peter Keng + Show 6 more

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https://doi.org/10.1074/jbc.m512624200

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Abstract

Osteoclasts are essential cells for bone erosion in inflammatory arthritis and are derived from cells in the myeloid lineage. Recently, we reported that tumor necrosis factor-alpha (TNFalpha) increases the blood osteoclast precursor (OCP) numbers in arthritic patients and animals, which are reduced by anti-TNF therapy, implying that circulating OCPs may have an important role in the pathogenesis of erosive arthritis. The aim of this study is to investigate the mechanism by which TNFalpha induces this increase in OCP frequency. We found that TNFalpha stimulated cell division and conversion of CD11b+/Gr-1-/lo/c-Fms- to CD11b+/Gr-1-/lo/c-Fms+ cells, which was not blocked by neutralizing macrophage colony-stimulating factor (M-CSF) antibody. Ex vivo analysis of monocytes demonstrated the following: (i) blood CD11b+/Gr-1-/lo but not CD11b-/Gr-1- cells give rise to osteoclasts when they were cultured with receptor activator NF-kappaB ligand and M-CSF; and (ii) TNF-transgenic mice have a significant increase in blood CD11b+/Gr-1-/lo cells and bone marrow proliferating CD11b+/Gr-1-/lo cells. Administration of TNFalpha to wild type mice induced bone marrow CD11b+/Gr-1-/lo cell proliferation, which was associated with an increase in CD11b+/Gr-1-/lo OCPs in the circulation. Thus, TNFalpha directly stimulates bone marrow OCP genesis by enhancing c-Fms expression. This results in progenitor cell proliferation and differentiation in response to M-CSF, leading to an enlargement of the marrow OCP pool. Increased marrow OCPs subsequently egress to the circulation, forming a basis for elevated OCP frequency. Therefore, the first step of TNF-induced osteoclastogenesis is at the level of OCP genesis in the bone marrow, which represents another layer of regulation to control erosive disease.

Highlights

Resorption in this process has been proven in studies with various knock-out mice deficient in genes essential for osteoclastogenesis, which develop osteopetrosis because of the accumulation of un-resorbed bone matrix within the bone marrow cavity [1, 2]
The sorted cells were cultured with macrophage-colony-stimulating factor (M-CSF) and RANKL to generate osteoclasts that were assessed by tartrateresistant acid phosphatase (TRAP) staining
Because it is likely that marrow CD11bϪ cells differentiate to TRAPϩ osteoclasts through the CD11bϩ stage and only blood CD11bϩ/ Gr-1Ϫ/lo cells give rise to osteoclasts, we reasoned that CD11bϩ/Gr1Ϫ/lo cells include the majority of osteoclast precursor (OCP) and can be used as OCP surface markers

Summary

Introduction

Resorption in this process has been proven in studies with various knock-out mice deficient in genes essential for osteoclastogenesis, which develop osteopetrosis because of the accumulation of un-resorbed bone matrix within the bone marrow cavity [1, 2]. In patients or animals with RA, these precursor cells constantly migrate to inflamed joints perhaps from the following two directions: “outside in,” from blood to the pannus-bone interface, and “inside out,” from epiphysial bone marrow to the subchondral bone They differentiate to mature osteoclasts in response to high levels of osteoclastogenic cytokines, including receptor activator NF-␬B ligand (RANKL), macrophage-colony-stimulating factor (M-CSF), and tumor necrosis factor-␣ (TNF␣), produced by inflammatory cells in the synovium [7, 8]. TNF␣ Increases Osteoclast Precursors through c-Fms mice that develop erosive arthritis featured with intense synovial inflammation and destruction of cartilage and bone [12] These mice have increased numbers of OCPs in spleen and blood and increased numbers of mature osteoclasts in the affected joints [13]. Our results reveal a new mechanism for TNF␣ in the control of peripheral osteoclast numbers and provide an additional regulatory step to control osteoclast formation and bone resorption in inflammatory erosive diseases

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