Molecular determinants for the polarization of macrophage and osteoclast

Abstract

Emerging evidence suggest that macrophage and osteoclast are two competing differentiation outcomes from myeloid progenitors. In this review, we summarize recent advances in the understanding of the molecular mechanisms controlling the polarization of macrophage and osteoclast. These include nuclear receptors/transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and estrogen-related receptor α (ERRα), their transcription cofactor PPARγ coactivator 1-β (PGC-1β), metabolic factors such as mitochondrial complex I (CI) component NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4), as well as transmembrane receptors such as very-low-density-lipoprotein receptor (VLDLR). These molecular rheostats promote osteoclast differentiation but suppress proinflammatory macrophage activation and inflammation, by acting lineage-intrinsically, systemically or cross generation. These findings provide new insights to the understanding of the interactions between innate immunity and bone remodeling, advancing the field of osteoimmunology.

Keywords: Bone; ERRα; Macrophage; Ndufs4; Osteoclast; Osteoimmunology; PGC-1β; PPARγ; VLDLR.

Figure 1

Macrophage and osteoclast are two competing differentiation outcomes from myeloid progenitors. The polarization of macrophage and osteoclast is regulated by molecular rheostats. Peroxisome proliferator-activated receptor γ (PPARγ) and its ligand rosiglitazone (Rosi), estrogen-related receptor α (ERRα) and its endogenous agonist cholesterol (Chol), PPARγ coactivator 1-β (PGC-1β), mitochondrial complex I (CI) component NADH: ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4), as well as maternal very-low-density-lipoprotein receptor (VLDLR) act as rheostats to promote osteoclast differentiation but suppress proinflammatory macrophage activation and inflammation, by acting lineage-intrinsically, systemically or cross generation. M-CSF, macrophage colony-stimulating factor; RANKL, receptor activator of nuclear factor-κB ligand.