Induction of Osteoclast Differentiation by Runx2 through Receptor Activator of Nuclear Factor-κB Ligand (RANKL) and Osteoprotegerin Regulation and Partial Rescue of Osteoclastogenesis in Runx2–/– Mice by RANKL Transgene
Copyright policy )Induction of Osteoclast Differentiation by Runx2 through Receptor Activator of Nuclear Factor-κB Ligand (RANKL) and Osteoprotegerin Regulation and Partial Rescue of Osteoclastogenesis in Runx2–/– Mice by RANKL Transgene
Receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), and macrophage-colony stimulating factor play essential roles in the regulation of osteoclastogenesis. Runx2-deficient (Runx2-/-) mice showed a complete lack of bone formation because of maturational arrest of osteoblasts and disturbed chondrocyte maturation. Further, osteoclasts were absent in these mice, in which OPG and macrophage-colony stimulating factor were normally expressed, but RANKL expression was severely diminished. We investigated the function of Runx2 in osteoclast differentiation. A Runx2-/- calvaria-derived cell line (CA120-4), which expressed OPG strongly but RANKL barely, severely suppressed osteoclast differentiation from normal bone marrow cells in co-cultures. Adenoviral introduction of Runx2 into CA120-4 cells induced RANKL expression, suppressed OPG expression, and restored osteoclast differentiation from normal bone marrow cells, whereas the addition of OPG abolished the osteoclast differentiation induced by Runx2. Addition of soluble RANKL (sRANKL) also restored osteoclast differentiation in co-cultures. Forced expression of sRANKL in Runx2-/- livers increased the number and size of osteoclast-like cells around calcified cartilage, although vascular invasion into the cartilage was superficial because of incomplete osteoclast differentiation. These findings indicate that Runx2 promotes osteoclast differentiation by inducing RANKL and inhibiting OPG. As the introduction of sRANKL was insufficient for osteoclast differentiation in Runx2-/- mice, however, our findings also suggest that additional factor(s) or matrix protein(s), which are induced in terminally differentiated chondrocytes or osteoblasts by Runx2, are required for osteoclastogenesis in early skeletal development.
- Osaka University Japan
- Biomedical Research Institute United States
- University of Tokyo Japan
- Saitama Prefecture Japan
- Osaka Gakuin University Japan
Mice, Knockout, Membrane Glycoproteins, Receptor Activator of Nuclear Factor-kappa B, RANK Ligand, Osteoprotegerin, Osteoclasts, Receptors, Cytoplasmic and Nuclear, Cell Differentiation, Core Binding Factor Alpha 1 Subunit, Receptors, Tumor Necrosis Factor, Cell Line, Neoplasm Proteins, Mice, Gene Expression Regulation, Animals, Transgenes, Carrier Proteins, Glycoproteins, Signal Transduction, Transcription Factors
Mice, Knockout, Membrane Glycoproteins, Receptor Activator of Nuclear Factor-kappa B, RANK Ligand, Osteoprotegerin, Osteoclasts, Receptors, Cytoplasmic and Nuclear, Cell Differentiation, Core Binding Factor Alpha 1 Subunit, Receptors, Tumor Necrosis Factor, Cell Line, Neoplasm Proteins, Mice, Gene Expression Regulation, Animals, Transgenes, Carrier Proteins, Glycoproteins, Signal Transduction, Transcription Factors
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