Regulation of human osteoclast development by dendritic cell-specific transmembrane protein (DC-STAMP)

1Allergy/Immunology & Rheumatology Division, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave., Rochester, NY 14642, USA
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research (Impact Factor: 6.83). 01/2012; 27(1). DOI: 10.1002/jbmr.531
Source: PubMed


Osteoclasts (OC) are bone-resorbing, multinucleated cells that are generated via fusion of OC precursors (OCP). The frequency of OCP is elevated in patients with erosive inflammatory arthritis and metabolic bone diseases. Although many cytokines and cell surface receptors are known to participate in osteoclastogenesis, the molecular mechanisms underlying the regulation of this cellular transformation are poorly understood. Herein, we focused our studies on the dendritic cell-specific transmembrane protein (DC-STAMP), a seven-pass-transmembrane receptor-like protein known to be essential for cell-to-cell fusion during osteoclastogenesis. We identified an immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic tail of DC-STAMP, and developed an anti-DC-STAMP monoclonal antibody 1A2 that detected DC-STAMP expression on human tumor giant cells, blocked OC formation in vitro, and distinguished four patterns of human PBMC with a positive correlation to OC potential. In freshly isolated monocytes, DC-STAMP(high) cells produced a higher number of OC in culture than DC-STAMPlow cells and the surface expression of DC-STAMP gradually declined during osteoclastogenesis. Importantly, we showed that DC-STAMP is phosphorylated on its tyrosine residues and physically interacts with SHP-1 and CD16, an SH2-domain-containing tyrosine phosphatase and an ITAM-associated protein, respectively. Taken together, these data show that DC-STAMP is a potential OCP biomarker in inflammatory arthritis. Moreover, in addition to its effect on cell fusion, DC-STAMP dynamically regulates cell signaling during osteoclastogenesis. © 2011 American Society for Bone and Mineral Research.

Download full-text


Available from: David G Hicks,
  • Source
    • "Surprisingly, in the presence of RANKL and M-CSF, exposure of human monocytes to its monoclonal antibody 1A2 decreased phosphorylation of SHP-1 but increased PLC-g2 phosphorylation. Chiu et al. inferred that although an elevated PLC-g2 level might profit osteoclastogenesis, monocytes failing to form OC in the presence of 1A2 is due to a possible alteration of downstream calcium oscillations and the inhibition of the fusion of mOC (Chiu et al., 2012). As we suppose, the inhibition of fusion might also be related to the blocked internalization of DC-STAMP and increased transmembrane DC-STAMP. "
    [Show abstract] [Hide abstract]
    ABSTRACT: As a member of the mononuclear phagocyte system, osteoclasts (OC) absorb the bone matrix and participate in bone modeling by keeping a balance with osteoblasts (OB) and stromal cells. Mature OC derive from the fusion of mononuclear osteoclasts (mOC) and the fusion is considered as the indispensable process for the osteoclastogenesis and absorbing activity of OC. DC-STAMP (dendritic cell-specific transmembrane protein) has been validated playing a key role in the fusion of mOC. DC-STAMP is mainly expressed in OC, macrophages and dendritic cells (DC). While DC-STAMP was discovered in DC, more attentions have been paid to DC-STAMP in OC in this decade. This review will mainly focus on the function of DC-STAMP in OC. Studies on DC-STAMP in DC may also provide new sight for the study of DC-STAMP in OC. Since the function of DC-STAMP is still poorly understood and few studies have been implemented for illustration, many issues are still unknown and need to be revealed. We will also discuss these questions in this review.
    Journal of Cellular Physiology 10/2014; 229(10). DOI:10.1002/jcp.24553 · 3.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The factors that promote the localized bone resorption by giant cell tumor of bone (GCT) are not fully understood. We investigated whether T cells could contribute to bone resorption by stimulating expression of genes for parathyroid hormone-related protein (PTHrP), matrix metalloproteinase (MMP)-13, and the receptor activator of nuclear-factor κB ligand (RANKL). Two cell lines, Jurkat clone E6-1 and D1.1, were co-cultured with isolated GCT stromal cells. Real-time PCR analyses demonstrated a significant increase of all three genes following 48h incubation, and PTHrP and MMP-13 gene expression was also increased at 24h. Further, we examined the expression of CD40 ligand (CD40L), a protein expressed by activated T cells, and its receptor, CD40, in GCT. Immunohistochemistry results revealed expression of the CD40 receptor in both the stromal cells and giant cells of the tumor. RNA collected from whole GCT tissues showed expression of CD40LG, which was absent in cultured stromal cells, and suggests that CD40L is expressed within GCT. Stimulation of GCT stromal cells with CD40L significantly increased expression of the PTHrP and MMP-13 genes. Moreover, we show that inhibition of PTHrP with neutralizing antibodies significantly decreased MMP13 expression by the stromal cells compared to IgG-matched controls, whereas stimulation with PTHrP (1-34) increased MMP-13 gene expression. These results suggest that T cells may potentiate the catabolic effect of GCT.
    Biochemical and Biophysical Research Communications 02/2012; 419(4):719-23. DOI:10.1016/j.bbrc.2012.02.086 · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 μM) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the "housekeeping" a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein L-plastin was altered in cells treated with 50 μM enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments.
    Journal of Biological Chemistry 04/2012; 287(21):17894-904. DOI:10.1074/jbc.M111.280511 · 4.57 Impact Factor
Show more