| First Author | Yang T | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 18 | Pages | 7336-41 |
| PubMed ID | 23589896 | Mgi Jnum | J:196660 |
| Mgi Id | MGI:5488999 | Doi | 10.1073/pnas.1219748110 |
| Citation | Yang T, et al. (2013) E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-beta in the bone microenvironment. Proc Natl Acad Sci U S A 110(18):7336-41 |
| abstractText | TGF-beta 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-beta bioavailability by attenuating maturation of pro-TGF-beta during cartilage homeostasis. However, whether regulation of intracellular TGF-beta 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-beta/pro-TGF-beta ratio, with increased expression of TGF-beta 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 kappaB ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-beta antibody, significantly improved the low bone mass of Esl-1(-/-) mice, suggesting that elevated TGF-beta 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-beta maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling. |
