CD200R/CD200 Inhibits Osteoclastogenesis: New Mechanism of Osteoclast Control by Mesenchymal Stem Cells in Human

Audrey Varin,Luc Sensebé,Frédéric Deschaseaux,Elodie Labat,Charalampos Pontikoglou,Zoran Ivanovic

doi:10.1371/journal.pone.0072831

Abstract

Bone homeostasis is maintained by the balance between bone-forming osteoblasts and bone-degrading osteoclasts. Osteoblasts have a mesenchymal origin whereas osteoclasts belong to the myeloid lineage. Osteoclast and osteoblast communication occurs through soluble factors secretion, cell-bone interaction and cell–cell contact, which modulate their activities. CD200 is an immunoglobulin superfamilly member expressed on various types of cells including mesenchymal stem cells (MSCs). CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes/macrophages. We assume that CD200 could be a new molecule involved in the control of osteoclastogenesis and could play a role in MSC–osteoclast communication in humans. In this study, we demonstrated that soluble CD200 inhibited the differentiation of osteoclast precursors as well as their maturation in bone-resorbing cells in vitro. Soluble CD200 did not modify the monocyte phenotype but inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL) signaling pathway as well as the gene expression of osteoclast markers such as osteoclast-associated receptor (OSCAR) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, MSCs inhibited osteoclast formation, which depended on cell–cell contact and was associated with CD200 expression on the MSC surface. Our results clearly demonstrate that MSCs, through the expression of CD200, play a major role in the regulation of bone resorption and bone physiology and that the CD200-CD200R couple could be a new target to control bone diseases.

Highlights

Bone is a highly dynamic tissue that is constantly remodeled by a process involving bone resorption by osteoclasts and bone formation by osteoblasts
Recombinant CD200 inhibits osteoclast formation The CD200–CD200 receptor (CD200R) interaction can deliver an inhibitory signal to monocytes/macrophages [18,19]
To determine the effect of CD200 on osteoclastogenesis, we used a validated culture system: peripheral blood mononuclear cells (PBMCs) were cultivated for 2 days with macrophage colonystimulating factor (M-CSF) to induce RANK expression and treated with RANK ligand (RANKL) + MCSF for 21 days to induce the formation of multinucleated TRAP+ osteoclast-like cells capable of resorbing bone surface (Figure 1A,B)

Summary

Introduction

Bone is a highly dynamic tissue that is constantly remodeled by a process involving bone resorption by osteoclasts and bone formation by osteoblasts. Osteoclasts originate from hematopoietic lineage cells derived from bone-marrow myeloid precursors or circulating monocytes. Activation of NFATc1, the master gene of the osteoclast differentiation [5], leads to the expression of genes involved in osteoclast activation such as tartrate-resistant acid phosphatase (trap), Osteoclast-associated receptor (oscar) and cathepsin K (ctsk) [6,7]. Osteoblasts express both M-CSF and RANKL and modulate osteoclast activity. They express osteoprotegerin (OPG), which acts as a decoy receptor for RANK/RANKL binding. The balance between bone resorption and bone formation is mediated by soluble factors, but osteoblasts and osteoclasts can directly interact for regulation of bone homeostasis

Methods

Results

Conclusion