CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts

Abstract

Fusion of macrophages is an essential step in the differentiation of osteoclasts, which play a central role in the development and remodeling of bone. Osteoclasts are important mediators of bone loss, which leads, for example, to osteoporosis. Macrophage fusion receptor/signal regulatory protein ␣ (MFR/SIRP␣) and its ligand CD47, which are members of the Ig superfamily (IgSF), have been implicated in the fusion of macrophages. We show that CD200, which is not expressed in cells that belong to the myeloid lineage, is strongly expressed in macrophages at the onset of fusion. By contrast, the CD200 receptor (CD200R), which, like CD200, belongs to the IgSF, is expressed only in cells that belong to the myeloid lineage, including osteoclasts, and in CD4 ؉ T cells. Osteoclasts from CD200 ؊/؊ mice differentiated at a reduced rate. Activation of the NF-B and MAP kinase signaling pathways downstream of RANK, a receptor that plays a central role in the differentiation of osteoclasts, was depressed in these cells. A soluble recombinant protein that included the extracellular domain of CD200 rescued the fusion of CD200 ؊/؊ macrophages and their activation downstream of RANK. Conversely, addition of a soluble recombinant protein that included the extracellular domain of CD200R or short-hairpin RNA-mediated silencing of the expression of CD200R prevented fusion. Thus CD200 engagement of the CD200R at the initiation of macrophage fusion regulated further differentiation to osteoclasts. Consistent with in vitro observations, CD200 ؊/؊ mice contained fewer osteoclasts and accumulated more bone than CD200 ؉/؉ mice. The CD200-CD200R axis is therefore a putative regulator of bone mass, via the formation of osteoclasts.fusion ͉ macrophage ͉ RANK ͉ MAPK

Sorting of growth plate chondrocytes allows the isolation and characterization of cells of a defined differentiation status

“…Interestingly, CD200 is an immunomodulatory molecule potentially suppressing inflammation and autoimmune destruction, as well as osteoclast differentiation. (38)(39)(40) The juvenile growth plate is a continuously remodeling tissue in which hypertrophic cells secrete not only matrix metalloproteinases for degradation of the cartilage matrix (34,41) but also vascular endothelial growth factor that induces invasion of bone marrow sprouts. (42) While a portion of the hypertrophic chondrocytes undergoes apoptosis, endochondral bone is deposited on the scaffold of residual spicules of hypertrophic cartilage.…”

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

“…For example, CD200 expression is significantly upregulated prior to fusion of proliferating monocytes and subsequently enhances RANKL signaling, which promotes fusion. 8 Meanwhile, an inhibitory CD200 receptor (CD200R) is induced by lymphoid cells, ie, natural killer and activated T cells. 9 The dual function of CD200 suggests the existence of an "OC checkpoint," which downregulates immune effector cells.…”

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

“…Defective fusion of macrophages and osteoclasts was also demonstrated in MCP-1/CCL2 or ATP6v0d2 knock-out cells (14,15). In studies of osteoclasts employing neutralizing antibody and knock-out mice, respectively, E-cadherin and CD200 were reported to play a role in cell-cell fusion (16,17). Recently, two multimembrane-spanning molecules, dendritic cell-specific transmembrane protein (DC-STAMP) and osteoclast stimulatory transmembrane protein (OC-STAMP), were identified as required for cell-cell fusion of both macrophages and osteoclasts by generating knock-out mice (18,19).…”