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

Abstract

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-STAMPhigh 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.

Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis

“…Because DC-STAMP is known to be involved in the fusion of osteoclast precursors (42, 46 -48), the change could be linked functionally to the reduction in multinuclear and giant cells detected in enoxacintreated cultures. Levels of cell surface DC-STAMP have been shown to gradually decline during osteoclastogenesis (49). These results indicate that enoxacin influences DC-STAMP toward a cell surface expression pattern of DC-STAMP associated with less mature osteoclasts.…”

Osteoclast Fusion: Time‐Lapse Reveals Involvement of CD47 and Syncytin‐1 at Different Stages of Nuclearity

“…Numerous molecular factors have been identified over the years, which primarily play a major role in the preparative steps required for fusion. The most prominent of these is DC‐STAMP (dendritic cell‐specific transmembrane protein) (Kukita et al, 2004; Yagi et al, 2005; Iwasaki et al, 2008; Mensah et al, 2010; Chiu et al, 2012; Chiu and Ritchlin, 2016), which has been identified as one of the most essential single factors supporting both differentiation and fusion. However, also other factors such as CD47 (Han et al, 2000; Lundberg et al, 2007; Maile et al, 2011; Koskinen et al, 2013; Hobolt‐Pedersen et al, 2014), syncytin‐1 (Soe et al, 2011), OC‐STAMP (osteoclast stimulatory transmembrane protein) (Miyamoto et al, 2012; Witwicka et al, 2015), dynamin (Shin et al, 2014; Verma et al, 2014), Pin1 (peptidyl‐prolyl cis‐trans isomerase NIMA‐interacting 1) (Islam et al, 2014; Cho et al, 2015), and e‐cadherin (Mbalaviele et al, 1995; Fiorino and Harrison, 2016) are involved in OC fusion, but it is important to stress that this list is not exhaustive.…”

Osteoprotegerin Expressed by Osteoclasts

“…Bone-resorbing activity of mononuclear osteoclasts is lower than that of multinucleated osteoclasts (Yagi et al, 2005;Miyamoto, 2011;Chiu et al, 2012). In addition, TRAP activities in multinucleated osteoclastic giant cells of medium size are size-dependent, and the large cells reveal, in part, low activities (Metze et al, 1987).…”