Cell-Cell Fusion Mechanisms in Osteoclast Differentiation

Osteoclasts are specialised multinucleated cells responsible for bone resorption and are formed by the sequential fusion of mononuclear precursors under the influence of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). Initiation of fusion requires upregulation of fusogenic proteins such as dendritic cell–specific transmembrane protein (DC-STAMP) and osteoclast stimulatory transmembrane protein (OC-STAMP), alongside local remodelling of membrane lipids. Exposure of phosphatidylserine and phosphatidylethanolamine on the outer leaflet of the plasma membrane creates fusogenic domains, which recruit annexins and other binding partners to stabilise merger of bilayers. A coordinated cascade involving non-apoptotic activation of caspases, lipid scramblases, cytoskeletal reorganisation and cell-surface chaperones then drives successive fusion events, yielding a resorptive syncytium. Emerging data reveal that RNA-binding proteins and non-coding RNAs fine-tune stage-specific fusion activity, while feedback loops terminate fusion once an appropriate nuclearity is achieved. Defects in any of these steps can lead to osteopetrotic or osteoporotic phenotypes, emphasising the clinical importance of understanding fusion mechanisms for therapeutic targeting in skeletal diseases.

Research from Nature Portfolio

Recent studies have uncovered a novel role for the La protein in osteoclast fusion. During precursor differentiation, La protein reappears at the cell surface as a truncated species, where it interacts with annexin A5 and surface-exposed phosphatidylserine to promote membrane coalescence. Restoration of nuclear La at late stages acts as an off-switch for further fusion, indicating a precise temporal control of fusogenic activity. Earlier foundational work demonstrated that dynamic redistribution of phosphatidylethanolamine is essential for fusion, with upregulation of a biosynthetic acyltransferase (LPEAT2) and ABC transporters (ABCB4, ABCG1) driving enrichment of this lipid in filopodia at contact sites. Interruption of these lipid-remodelling pathways impairs precursor merging and yields mononuclear or poorly resorptive osteoclasts, highlighting the integrated roles of both proteins and lipids in orchestrating cell-cell fusion.

Cell-Cell Fusion Mechanisms in Osteoclast Differentiation publication trend

The graph below shows the total number of articles in cell-cell fusion mechanisms in osteoclast differentiation across all publications each year (not limited to Nature Index journals).

Technical terms

Osteoclast: A multinucleated bone-resorbing cell formed by fusion of mononuclear precursors under M-CSF and RANKL stimulation.

RANKL: A cytokine that binds the RANK receptor on precursors, initiating signalling cascades leading to fusion and differentiation.

Phosphatidylserine (PS): An anionic phospholipid normally on the inner leaflet that, when externalised, acts as a signal for membrane fusion.

DC-STAMP: A multi-pass transmembrane protein essential for the fusion competence of osteoclast precursors.

Scramblase (Xkr8): A membrane enzyme activated by non-apoptotic caspases to randomise phospholipid distribution and expose PS.

Long non-coding RNA (DLEU1): A regulatory RNA species that modulates early fusion events by influencing membrane dynamics and cytoskeletal interactions.

References

1. Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis. Nature Communications (2023).
2. Phosphatidylethanolamine dynamics are required for osteoclast fusion. Scientific Reports (2017).
3. Caspase-8 promotes scramblase-mediated phosphatidylserine exposure and fusion of osteoclast precursors. Bone Research (2024).
4. Stage-specific modulation of multinucleation, fusion, and resorption by the long non-coding RNA DLEU1 and miR-16 in human primary osteoclasts. Cell Death & Disease (2024).
5. Cell-surface phosphatidylserine regulates osteoclast precursor fusion. Journal of Biological Chemistry (2017).
6. Osteoclast Multinucleation: Review of Current Literature. International Journal of Molecular Sciences (2020).