Moonlighting osteoclasts as undertakers of apoptotic cells

Abstract

Rapid clearance of apoptotic cells, frequently referred to as efferocytosis, is crucial for the maintenance of tissue homeostasis and the prevention of autoimmunity. The common model of apoptotic cell clearance involves a system of released “Find me” and exposed “Eat me” signals on apoptotic cells, detected and recognized by matching receptors on macrophages or dendritic cells (DC), referred to as the phagocytic synapse. Osteoclasts share the monocyte lineage with these professional mononuclear phagocytes, thus raising the question if, in addition to bone resorption, osteoclasts can act as scavengers for apoptotic cells. Our qPCR data clearly show that osteoclasts express most of the genes required for dying cell clearance at mRNA levels similar to or even higher than those observed in M1-macrophages, M2-macrophages or DC. Our microscopical analyses reveal that osteoclasts in fact can bind and/or engulf apoptotic cells in an essentially serum-independent fashion. Together with our data on the abundance of the respective mRNAs, these results identify the vitronectin receptor (integrin α_νβ₃)/milk fat globule-EGF factor 8 protein (MFG-E8) axis, the scavenger receptors (CD36, CD68 and class A macrophage scavenger receptor (SR-A)), the complement/complement receptor axis, the Mer/Tyro3/Protein S axis, and the phosphatidylserine (PS) receptor brain-specific angiogenesis inhibitor 1 (BAI1) as the most promising candidates to be involved in osteoclast-mediated efferocytosis.

Keywords::

• Osteoclasts
• phagocytosis
• efferocytosis
• dying cell clearance
• apoptotic cell clearance
• rheumatoid arthritis

Acknowledgements

This study was supported by the Bundesministerium für Bildung und Forschung (BMBF; project ANCYLOSS), the DFG (SFB685 and SFB914), LMU excellent and the Universität Bayern e.V. U.H. is supported by DFG-Graduiertenkolleg 1660.

Author contributions are as follows: K.P. performed monocyte elutriation; H.K. performed qPCRs; U.H. and N.I. performed phagocytosis assays; U.H. performed microscopy; and U.H., A.D., G.S., M.H., and K.L. designed the study, analyzed the data, and wrote the paper. All authors discussed the results and commented on the manuscript.

Declaration of interest : The authors declare no competing financial interests. The authors are responsible for the content and the writing of this paper.