title: A Liver-Bone Endocrine Relay by IGFBP1 Promotes Osteoclastogenesis and Mediates FGF21-Induced Bone Resorption.
abstract: Fibroblast growth factor 21 (FGF21) promotes insulin sensitivity but causes bone loss. It elevates bone resorption by an undefined non-osteoclast-autonomous mechanism. We have detected a pro-osteoclastogenic activity in the hepatic secretome that is increased by FGF21 and largely attributed to insulin-like growth factor binding protein 1 (IGFBP1). Ex vivo osteoclast differentiation and in vivo bone resorption are both enhanced by recombinant IGFBP1 but suppressed by an IGFBP1-blocking antibody. Anti-IGFBP1 treatment attenuates ovariectomy-induced osteoporosis and abolishes FGF21-induced bone loss while maintaining its insulin-sensitizing metabolic benefit. Mechanistically, IGFBP1 functions via its RGD domain to bind to its receptor integrin β1 on osteoclast precursors, thereby potentiating RANKL-stimulated Erk-phosphorylation and NFATc1 activation. Consequently, osteoclastic integrin β1 deletion confers resistance to the resorption-enhancing effects of both IGFBP1 and FGF21. Therefore, the hepatokine IGFBP1 is a critical liver-bone hormonal relay that promotes osteoclastogenesis and bone resorption as well as an essential mediator of FGF21-induced bone loss.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xunde
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jing Y
authors.initials: JY
authors.lastname: Krzeszinski
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: yihong.wan@utsouthwestern.edu.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy / Q000009:adverse effects; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C032231:IGFBP1 protein, human; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D053245:RANK Ligand; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors