Dendritic Cell‐Specific Transmembrane Protein (DC‐STAMP) Regulates Osteoclast Differentiation via the Ca²⁺/NFATc1 Axis

Abstract

DC-STAMP is a multi-pass transmembrane protein essential for cell-cell fusion of osteoclast precursors during osteoclast (OC) development. DC-STAMP−/− mice have mild osteopetrosis and form mononuclear cells with limited resorption capacity. The identification of an Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) on the cytoplasmic tail of DC-STAMP suggested a potential signaling function but the absence of known DC-STAMP ligand has hindered examination of downstream signaling pathways. To address this problem, we engineered a light-activatable DC-STAMP chimeric molecule in which light exposure mimics ligand engagement that can be traced by downstream Ca2+ signaling. Deletion of the cytoplasmic ITIM resulted in a significant elevation in the amplitude and duration of intracellular Ca2+ flux. We also found that decreased NFATc1 expression in DC-STAMP−/− cells was restored by DC-STAMP over-expression. Multiple biological phenotypes including cell-cell fusion, bone erosion, cell mobility, DC-STAMP cell surface distribution, and NFATc1 nuclear translocation were altered by deletion of the ITIM and adjacent amino acids. In contrast, mutations on each of tyrosine residues in the ITIM showed no effect on DC-STAMP function. Collectively, our results suggest that ITIM on DC-STAMP is a functional motif that regulates osteoclast differentiation through the NFATc1 / Ca2+ axis.

Pregnenolone Inhibits Osteoclast Differentiation and Protects Against Lipopolysaccharide-Induced Inflammatory Bone Destruction and Ovariectomy-Induced Bone Loss

“…The efficient early activation NF-kB and MAPK is necessary for the downstream induction and upregulation of transcription factors c-Fos and NFATc1. Importantly, NFATc1 has been regarded as the master transcription factor for osteoclast formation and function, transcriptionally regulating the expression of various osteoclast genes including DC-STAMP, ATP6V0d2, TRAP, CTSK, and NFATc1 itself (Kim et al, 2008;Kim et al, 2013;Liu et al, 2016;Chiu et al, 2017;Zeng et al, 2017;Pang et al, 2019). As with the loss of early signaling events, the lack of either c-Fos or NFATc1 results in abolishment of osteoclast formation leading to increase bone mass and osteopetrosis in mice (Asagiri et al, 2005;Arai et al, 2012;Toray et al, 2017).…”

Targeted sequencing of DCSTAMP in familial Paget's disease of bone

“…Genetic ablation of DCSTAMP in mice impairs osteoclast fusion and thus attenuates bone resorption ( Yagi et al, 2005 ). An Immunoreceptor Tyrosine-based Inhibitory motif has been identified on the cytoplasmic tail of DC-STAMP, suggestive of a signalling role, and deletion of this tail appears to prevent nuclear translocation of the critical osteoclast transcription factor NFATc1 ( Chiu et al, 2017 ). In addition, NFATc1 expression is reduced in DCSTAMP knockout cells ( Chiu et al, 2017 ).…”

Effect of a rare genetic variant of TM7SF4 gene on osteoclasts of patients with Paget’s disease of bone

“…In vitro studies should be undertaken to investigate the role of the rare genetic variant on the expression of DC-STAMP at different times during osteoclastogenesis and under different conditions such as with a gradient of concentration of RANKL or by the use of cocultures of osteoclast precursors with stromal cells to reproduce more physiological conditions like in the bone microenvironment. The folding of the protein and the impact of the rare variant, located in the seventh and last transmembrane domain of the protein, on the Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM)-mediated signaling of the cytoplasmic tail of DC-STAMP should also be further studied [ 37 ].…”