Proceedings of the National Academy of Sciences - PNAS, 2013-04, Vol.110 (18), p.7336-7341
2013
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- Autor(en) / Beteiligte
- Titel
- E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2013-04, Vol.110 (18), p.7336-7341
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2013
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro–TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1 ⁻/⁻ mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1 ⁻/⁻ osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1 ⁻/⁻ osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast–osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1 ⁻/⁻ calvaria exhibit an elevated mature TGF-β/pro–TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan–TGF-β antibody, significantly improved the low bone mass of Esl-1 ⁻/⁻ mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1 ⁻/⁻ mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast–osteoclast coupling.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1219748110Titel-ID: cdi_pubmed_primary_23589896
- Format
- –
- Schlagworte
- Animals, Antibodies, Antibodies - pharmacology, Bioavailability, Biological Sciences, Bone Diseases, Metabolic - complications, Bone Diseases, Metabolic - metabolism, Bone Diseases, Metabolic - pathology, Bone Diseases, Metabolic - physiopathology, Bone remodeling, Bone Remodeling - drug effects, Bone Remodeling - genetics, Bone resorption, Bone Resorption - complications, Bone Resorption - genetics, Bone Resorption - pathology, Bone Resorption - physiopathology, Bones, Calcification, Physiologic - drug effects, Calcification, Physiologic - genetics, Cell Differentiation - drug effects, Cell Differentiation - genetics, Cell Lineage - drug effects, Cell Lineage - genetics, Cells, Cultured, Femur, Femur - diagnostic imaging, Femur - drug effects, Femur - pathology, Femur - physiopathology, Gene Expression Profiling, Gene expression regulation, Gene Expression Regulation - drug effects, Homeostasis, Homeostasis - drug effects, Metabolic bone diseases, Mice, Organ Size - drug effects, Osteoblasts - drug effects, Osteoblasts - metabolism, Osteoblasts - pathology, Osteoclasts - drug effects, Osteoclasts - metabolism, Osteoclasts - pathology, Osteogenesis - drug effects, Osteogenesis - genetics, Phenotype, Radiography, Receptors, Receptors, Fibroblast Growth Factor - deficiency, Receptors, Fibroblast Growth Factor - metabolism, Sialoglycoproteins - deficiency, Sialoglycoproteins - metabolism, Signal Transduction - genetics, Transforming Growth Factor beta - metabolism