 Osteoclasts are multinucleated cells that were first described by the swiss-german histologist Albert von Koelliker in 1873. In his original publication, Koelliker writes:
“Assuming that the osteoclasts are simple, more or less amorphous cells whose nuclei were subject to a process of multiplication, the question remains as to how they are formed.”
Figure 1: “Osteoclast from the sinus frontalis of the calf, as if in the process of division, maybe also fused”. Adapted from Koelliker, 1873 [1]
Since Koelliker, the major role of osteoclasts as bone-resorbing cells and their function in innate immunity have been studied intensively. In contrast to Koelliker’s initial impression, we know today that osteoclast multinucleation arises from cell fusion rather than multiplication of the nucleus, much like it is the case for other multinucleated cells such as myofibers and trophoblastic cells. Additionally, individual components that are involved in the fusion process have been identified:
The fusion of the plasma membrane of neighboring cells depends on specific fusion proteins and receptors, such as proteins of the highly conserved syncytin family. Of note, syncytins originate from a retrovirus that was integrated into the mammalian genome around 25 million years ago [2]. As a retro-element, human Syncytin-1 represents the original envelope protein of the retrovirus, although its functional context has changed to facilitate cell fusion rather than viral entry into the cell.
Accumulation of a specific phospholipid, phosphatidylserine (PS), at the outer leaflet of the plasma membrane is critical for cell fusion [3]. PS exposure, however, is considered a hallmark feature of apoptosis and represents an eat-me signal for macrophages to dispose of the cellular remains.
Collectively, cellular fusion seems to rely on the repurposing of unrelated molecular pathways –intriguingly, one of these processes in question is meant to result in the cell’s own death. But what governs the ultimate decision between fusion or apoptosis?
In our study, we demonstrate that the activation of a specific set of caspases is responsible for a local and transient PS exposure. This spatially and temporally confined activation prevents whole-cell initiation of the cell death program while allowing the recognition of potential fusion partners during osteoclastogenesis [4]. Indeed, we could show that the activation of caspase-8 is a key event for osteoclast fusion (Fig. 2).
Figure 2: Fusing osteoclast precursors presenting accumulation of active caspase-8 (red), phalloidin in blue, DAPI in white [4].
Ultimately, the decision to either fuse with neighboring cells or undergo apoptosis lies in the strict local confinement of caspase activation – and as such, is in line with many things in life: dosis sola facit venenum – only the dose makes the poison.
References:
[1] Kölliker A. Die normale Resorption des Knochengewebes und Ihre Bedeutung für die Entstehung der Typischen Knochenformen. (1873). Available online at: https://archive.org/details/b22392610/page/n107
[2] Soygur, B., & Sati, L. The role of syncytins in human reproduction and reproductive organ cancers. Reproduction (2016).doi.org/10.1530/REP-16-0031
[3] Verma SK, Leikina E, Melikov K et al. Cell-surface phosphatidylserine regulates osteoclast precursor fusion. J Biol Chem. (2018) doi: 10.1074/jbc.M117.809681.
[4] Krishnacoumar, B., Stenzel, M., Garibagaoglu, H. et al. Caspase-8 promotes scramblase-mediated phosphatidylserine exposure and fusion of osteoclast precursors. Bone Res (2024). doi: 10.1038/s41413-024-00338-4