Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 18, Pages 7336-7341Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1219748110
Keywords
1D11 antibody; osteoblast mineralization; osteoporosis
Categories
Funding
- Arthritis Foundation postdoctoral fellowship
- pilot grant from The Rolanette and Berdon Lawrence Bone Disease Program of Texas
- National Institutes of Health [5P01HD070394, DE016990]
- Howard Hughes Medical Institute Foundation
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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 kappa B 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.
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