Bone Abstracts

Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that controls the engulfment of apoptotic cells and exerts anti-inflammatory effects. It has been implicated in the pathogenesis of several diseases, but its role in the bone microenvironment is still unknown. Here we tested the hypothesis that MFG-E8 also regulates bone metabolism and the development of arthritis.

MFG-E8 expression was detected in mouse bones and primary murine osteoblasts and osteoclasts. MFG-E8 expression levels in osteoblasts increased with cellular differentiation and reached a maximum after 14 days (3.4-fold). In osteoclasts, MFG-E8 expression increased up to 20-fold in mature osteoclasts. To elucidate whether MFG-E8 affects bone remodeling, we analyzed the bones from 6 weeks old MFG-E8-knockout (MFG-E8-KO) and wild-type (WT) mice. The trabecular bone mineral density at the lumbar spine in MFG-E8-KO mice was reduced by 10% (P<0.01) compared to WT mice. Serum levels of the bone formation marker P1NP were decreased by 37% (P<0.01) in MFG-E8-KO mice as were the mRNA levels of several osteoblast markers (Runx2, 50%; alkaline phosphatase, 60%; and osteocalcin, 75%). In contrast, bone marrow macrophages from MFG-E8-KO mice differentiated more effectively into osteoclasts compared to wild-type cells, producing threefold more osteoclasts.

To further determine whether MFG-E8 also plays a role in inflammatory arthritis, we subjected MFG-E8-KO and WT mice to the K/BxN serum transfer arthritis model and monitored signs of inflammation for 26 days. In the early arthritic phase, paws of WT and MFG-E8-KO mice showed similar signs of inflammation. However, by day 16 paws of MFG-E8-KO mice remained inflamed for a longer period of time compared to WT mice as reflected by a 15% increase in the paw thickness (P<0.01) and a 2 °C higher paw temperature (P<0.05).

Thus, these data indicate that MFG-E8 controls bone metabolism and inflammation in arthritis, and may represent a novel mediator of osteoimmunology.