Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2-/- mice by RANKL transgene
| Autor: | Naoko Kanatani, Tatsuya Furuichi, Ryo Fukuyama, Kanji Higashio, Hirayuki Enomoto, Kazuki Yano, Carolina A. Yoshida, Satoko Shiojiri, Kenji Takada, Toshihisa Komori, Kazuto Hoshi, Akira Zanma, Atsuko Mizuno, Reiko Nakamura, Hisataka Yasuda |
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| Rok vydání: | 2003 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty Cellular differentiation Osteoclasts Receptors Cytoplasmic and Nuclear Core Binding Factor Alpha 1 Subunit Biochemistry Chondrocyte Receptors Tumor Necrosis Factor Cell Line Mice stomatognathic system Osteoprotegerin Osteoclast Internal medicine medicine Animals Transgenes Molecular Biology Glycoproteins Mice Knockout Membrane Glycoproteins biology Receptor Activator of Nuclear Factor-kappa B Chemistry musculoskeletal neural and ocular physiology RANK Ligand Cell Differentiation Cell Biology musculoskeletal system Cell biology Neoplasm Proteins RUNX2 Endocrinology medicine.anatomical_structure Gene Expression Regulation RANKL biology.protein Signal transduction Carrier Proteins Signal Transduction Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 278(26) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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