DC-STAMP and OC-STAMP cooperatively regulate osteoclast and foreign body giant cell cell–cell fusion

TL;DR

This study shows that two proteins, DC-STAMP and OC-STAMP, work together to help form multi-nuclear cells like osteoclasts and foreign body giant cells, and their absence leads to increased bone formation.

Contribution

The study reveals that DC-STAMP and OC-STAMP cooperatively regulate cell fusion in osteoclasts and FBGCs, and their dual deficiency leads to increased osteogenesis.

Findings

Co-cultures of DC-STAMP or OC-STAMP knockout cells with wild-type cells still show normal cell fusion.

Co-cultures of DC-STAMP and OC-STAMP double knockout cells fail to undergo cell fusion.

DKO mice exhibit enhanced bone formation compared to wild-type mice.

Abstract

Osteoclasts and foreign body giant cells (FBGCs) are multi-nuclear cells established by fusion of their mono-nuclear forms. Multi-nucleation via cell–cell fusion is a common characteristic of osteoclasts and FBGCs, and Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) and Osteoclast Stimulatory Transmembrane Protein (OC-STAMP) are both required for the process. Thus, it is thought that DC-STAMP and OC-STAMP interaction likely induces this fusion, but details of these mechanisms are not clear.

We crossed DC-STAMP knockout (KO) with OC-STAMP KO mice to obtain DC-STAMP/OC-STAMP doubly deficient (DKO) mice. Osteoclasts and FBGC common progenitors were isolated from wild-type (WT), DC-STAMP KO, OC-STAMP KO or DKO mice. We then set up 4 co-culture systems: (1) WT with DC-STAMP KO cells, (2) WT with OC-STAMP KO cells, (3) WT with DKO cells, and (4) DC-STAMP KO with OC-STAMP KO cells to induce osteoclast or FBGC formation. We evaluated osteoclast and FBGC formation by TRAP and May–Gruenwald Giemsa staining, respectively. Finally, we performed bone morphometric analysis of WT, DC-STAMP KO, OC-STAMP KO, and DKO mice.

Cell–cell fusion occurs normally in co-cultures of DC KO with WT cells, OC KO with WT cells, and DKO with WT cells in both osteoclast and FBGC-inducing conditions. By contrast, co-cultures of DC-STAMP KO with OC-STAMP KO cells did not show cell–cell fusion. Bone morphometric analysis revealed enhanced bone formation in DKO mice.

DC-STAMP and OC-STAMP cooperate to promote osteoclast and FBGC cell–cell fusion. DC-STAMP and OC-STAMP doubly deficient mice exhibit increased osteogenesis.

The online version contains supplementary material available at 10.1007/s00774-025-01667-y.

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