Regulation of osteoclast homeostasis and inflammatory bone loss by MFG-E81

The glycoprotein milk fat globule-EGF factor 8 (MFG-E8) is expressed in several tissues and mediates diverse homeostatic functions. However, whether MFG-E8 plays a role in bone homeostasis has not been established. Here we show for the first time that osteoclasts express and are regulated by MFG-E8. Bone marrow-derived osteoclast precursors (OCPs) from MFG-E8–deficient ( Mfge8 −/− ) mice underwent increased RANKL-induced osteoclastogenesis leading to enhanced resorption pit formation as compared with wild-type controls. Consistently, exogenously added MFG-E8 inhibited RANKL-induced osteoclastogenesis from mouse or human OCPs. Upon induction of experimental periodontitis, an oral inflammatory disease characterized by loss of bone support of the dentition, Mfge8 −/− mice exhibited higher numbers of osteoclasts and more bone loss than wild-type controls. Accordingly, local microinjection of anti-MFG-E8 mAb exacerbated periodontal bone loss in wild-type mice. Conversely, microinjection of MFG-E8 inhibited bone loss in experimental mouse periodontitis. In comparison to wild-type controls, Mfge8 −/− mice also experienced >60% more naturally occurring chronic periodontal bone loss. In conclusion, MFG-E8 is a novel homeostatic regulator of osteoclasts and could be exploited therapeutically to treat periodontitis and perhaps other immunological disorders associated with inflammatory bone loss.