Moonlighting osteoclasts as undertakers of apoptotic cells

TLDR

Rapid clearance of apoptotic cells (efferocytosis) is essential for tissue homeostasis, and while macrophages and dendritic cells use “find me”/“eat me” signals to recognize dying cells, osteoclasts—sharing a monocyte lineage—may also serve as scavengers. Our qPCR and microscopy data demonstrate that osteoclasts express key efferocytosis genes at levels comparable to or exceeding those of macrophages and dendritic cells, can bind and engulf apoptotic cells independently of serum, and implicate the vitronectin receptor/MFG‑E8, CD36/CD68/SR‑A, complement, Mer/Tyro3/Protein S, and BAI1 pathways as major mediators of osteoclast‑driven efferocytosis.

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(ν)β(3))/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.