Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions

Abstract

Osteoclasts and foreign body giant cells (FBGCs) are derived from common progenitors and share properties such as multi-nucleation capacity induced by cell-cell fusion; however, mechanisms underlying lineage determination between these cells remain unclear. Here we show that, under inflammatory conditions, osteoclasts are stimulated in a manner similar to M1 macrophages, while formation of FBGCs, which exhibit M2-like phenotypes, is inhibited in a manner similar to that seen in M1/M2 macrophage polarization. FBGC/osteoclast polarization was inhibited by conditional knockout of tumor necrosis factor receptor associated factor 6 (Traf6) in adults in vivo and in vitro. Traf6-null mice were previously reported to die soon after birth, but we found that Traf6 deletion in adults did not cause lethality but rather inhibited osteoclast activation and prevented FBGC inhibition under inflammatory conditions. Accordingly, basal osteoclastogenesis was significantly inhibited by Traf6 deletion in vivo and in vitro and accompanied by increased bone mass. Lipopolysaccharide-induced osteoclast formation and osteolysis were significantly inhibited in Traf6 conditional knockout mice. Our results suggest that Traf6 plays a crucial role in regulating M1 osteoclast and M2 FBGC polarization and is a potential therapeutic target in blocking FBGC inhibition, antagonizing osteolysis in inflammatory conditions, and increasing bone mass without adverse effects in adults.

CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages

“…To evaluate the inhibitory effect of CTLA4-Ig on bone absorption in vivo, we used LPS-induced murine calvarian osteolysis model. (21) In short, 10-week-old female mice were injected with either 200 μL PBS (control), 200 μL of PBS containing LPS (Sigma-Aldrich; 25 μg per gram body weight), or 200 μL PBS containing LPS (25 μg/g) plus murine chimera CTLA4-Ig (2.5 μg per gram body weight) onto the surface of calvaria. Five days after the treatment, the surfaces of calvaria were examined by µCT (InspeXio SMX-100CT system; Shimadzu, Kyoto, Japan) as previously reported.…”

Pathophysiology Aspects of Muscle Atrophy and Osteopenia Induced by Chronic Constriction Injury (CCI) of the Sciatic Nerve in Rat

“…This gene could cause an alteration of the physiological bone remodelling [74]. In fact, the deletion of TRAF-6 is associated with an increase in the number of osteoblasts and a reduction of osteoclasts, as well as an increase in bone mineral density [75]. Two possible mechanisms may be involved in the pathogenesis of the osteoporosis/osteopenia associated with CCI.…”

Smoking cessation increases levels of osteocalcin and uncarboxylated osteocalcin in human sera

“…For BMD analysis, femurs were removed, fixed in 70% ethanol, and subjected to dual energy x-ray absorptiometric (DEXA) scanning to measure BMD (mg/cm 2 ) at proximal to distal points using a DCS-600R system (Aloka, Co. Ltd, Tokyo, Japan). Bone morphometric analysis and tartrate-resistant acid phosphatase (TRAP) staining were performed in tibiae, as described 25 .…”