E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7336-41. doi: 10.1073/pnas.1219748110. Epub 2013 Apr 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Bone Diseases, Metabolic / complications
  • Bone Diseases, Metabolic / metabolism
  • Bone Diseases, Metabolic / pathology
  • Bone Diseases, Metabolic / physiopathology
  • Bone Remodeling* / drug effects
  • Bone Remodeling* / genetics
  • Bone Resorption / complications
  • Bone Resorption / genetics
  • Bone Resorption / pathology
  • Bone Resorption / physiopathology
  • Calcification, Physiologic / drug effects
  • Calcification, Physiologic / genetics
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Lineage / drug effects
  • Cell Lineage / genetics
  • Cells, Cultured
  • Femur / diagnostic imaging
  • Femur / drug effects
  • Femur / pathology
  • Femur / physiopathology
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Homeostasis / drug effects
  • 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, Fibroblast Growth Factor / deficiency
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Sialoglycoproteins / deficiency
  • Sialoglycoproteins / metabolism*
  • Signal Transduction / genetics
  • Transforming Growth Factor beta / metabolism*


  • Antibodies
  • Receptors, Fibroblast Growth Factor
  • Sialoglycoproteins
  • Transforming Growth Factor beta
  • cysteine-rich fibroblast growth factor receptor