title: TGF-β induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts.
abstract: In young adults, bone lost through osteoclast-mediated resorption is precisely replaced in both location and amount. Understanding how these two processes are coupled is crucial to advancing treatments for osteoporosis, a disease that progresses when the processes become uncoupled. We documented that osteoclasts secrete the mammalian integration 1 gene that is the homolog of Drosophila Wngless (Wnt) 10b, bone morphogenetic protein 6 (BMP6), and the chemokine sphingosin 1 phosphate (S1P) to promote mesenchymal cell mineralization in vitro. During bone resorption, TGF-β1 is released from the bone extracellular matrix and activated by osteoclasts. Thus, TGF-β1 levels are elevated during the resorption phase of bone turnover. We therefore investigated the influences of TGF-β1 on osteoclast-mediated support of mineralization. TGF-β1 increased osteoclast production of Wnt10b, but not BMP6 or S1P. Blocking Wnt10b activity with the Wnt signaling inhibitor Dickkoph-related protein 1 suppressed the ability of TGF-β-treated osteoclast-conditioned media to promote osteoblast mineralization. Examination of TGF-β signaling in osteoclasts revealed that induction of Wnt10b expression was dependent on Smad2/3 activation and independent from TGF-β1 stimulation of protein kinase B (AKT) or MAPK kinase. TGF-β1-treated osteoclast-conditioned media from cells with blocked Smad signaling exhibited a reduced ability to support mineralization, demonstrating the importance of Smad signaling in this response. Parallel cultures with suppressed TGF-β activation of AKT or MAPK kinase signaling retained their ability to elevate mineralization. These results demonstrate that TGF-β1 stimulates Wnt10b production in osteoclasts, which may enhance restoration of the bone lost during the resorptive phase of bone turnover.
authors.affiliation: Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. Oursler.merryjo@mayo.edu.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Ota
authors.forename: Patrick
authors.initials: P
authors.lastname: Quint
authors.forename: Ming
authors.initials: M
authors.lastname: Ruan
authors.forename: Larry
authors.initials: L
authors.lastname: Pederson
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
authors.forename: Merry Jo
authors.initials: MJ
authors.lastname: Oursler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism; D002113:Calcification, Physiologic; D002450:Cell Communication; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D017077:Culture Media, Conditioned; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D012333:RNA, Messenger; D051896:Smad Proteins, Receptor-Regulated; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; C060506:sphingosine 1-phosphate; D013110:Sphingosine