MFG-E8, a novel homeostatic regulator of osteoclastogenesis

George Hajishengallis

doi:10.14800/ics.285

Abstract

Although the glycoprotein MFG-E8 (milk fat globule-epidermal growth factor-factor 8) has been investigated extensively as an anti-inflammatory and homeostatic molecule, a possible role in bone homeostasis and disease was not addressed until recently. Our group has now shown that MFG-E8 is expressed by human and mouse osteoclasts and regulates their differentiation and function (Abe et al., J Immunol 2014;193:1383-1391). Whereas genetic deficiency or antibody-mediated neutralization of MFG-E8 enhances osteoclastogenesis and promotes inflammation-induced bone loss in mice, local administration of recombinant MFG-E8 blocks bone loss. These findings establish MFG-E8 as a novel homeostatic regulator of osteoclastogenesis and suggest that MFG-E8 could be exploited therapeutically to treat disorders associated with inflammatory bone loss, such as periodontitis and rheumatoid arthritis.

Highlights

The milk fat globule-epidermal growth factor (EGF)-factor 8 (MFG-E8; known as lactadherin) is a secreted glycoprotein expressed in a range of tissues by a variety of cells including macrophages, fibroblasts, dendritic and epithelial cells [1]
We showed that local gingival microinjection of recombinant MFG-E8 inhibited bone loss in WT mice subjected to ligature-induced periodontitis
Taken together with the strong connection between inflammation and osteoclastogenesis [18], our findings suggest that the therapeutic application of MFG-E8 is capable of a two-pronged attack on periodontitis and perhaps other inflammatory bone disorders

Summary

Introduction

The milk fat globule-epidermal growth factor (EGF)-factor 8 (MFG-E8; known as lactadherin) is a secreted glycoprotein expressed in a range of tissues by a variety of cells including macrophages, fibroblasts, dendritic and epithelial cells [1]. Our group has recently shown that Del-1 acts homeostatically to regulate local inflammation in periodontitis [8], a biofilm-induced inflammatory disease causing loss of bone support of the dentition [9]. The resurgence of MFG-E8 expression correlated with the appearance of osteoclasts (OCLs), giant multinucleated cells (MNCs) that resorb bone during physiological bone remodeling and under pathologic inflammatory conditions (e.g., rheumatoid arthritis and periodontitis) that greatly potentiate their resorptive activity [12,13].

Results

Conclusion