title: E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Ingo
authors.initials: I
authors.lastname: Grafe
authors.forename: Yangjin
authors.initials: Y
authors.lastname: Bae
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Terry K
authors.initials: TK
authors.lastname: Bertin
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.forename: Catherine G
authors.initials: CG
authors.lastname: Ambrose
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001851:Bone Diseases, Metabolic / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics; D001862:Bone Resorption / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D011859:Radiography; D017468:Receptors, Fibroblast Growth Factor / Q000172:deficiency / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000906:Antibodies; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; C086711:cysteine-rich fibroblast growth factor receptor