title: Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2.
abstract: Wnt signalling is a key pathway controlling bone formation in mice and humans. One of the regulators of this pathway is Dkk1, which antagonizes Wnt signalling through the formation of a ternary complex with the transmembrane receptors Krm1/2 and Lrp5/6, thereby blocking the induction of Wnt signalling by the latter ones. Here we show that Kremen-2 (Krm2) is predominantly expressed in bone, and that its osteoblast-specific over-expression in transgenic mice (Col1a1-Krm2) results in severe osteoporosis. Histomorphometric analysis revealed that osteoblast maturation and bone formation are disturbed in Col1a1-Krm2 mice, whereas bone resorption is increased. In line with these findings, primary osteoblasts derived from Col1a1-Krm2 mice display a cell-autonomous differentiation defect, impaired canonical Wnt signalling and decreased production of the osteoclast inhibitory factor Opg. To determine whether the observed effects of Krm2 on bone remodeling are physiologically relevant, we analyzed the skeletal phenotype of 24 weeks old Krm2-deficient mice and observed high bone mass caused by a more than three-fold increase in bone formation. Taken together, these data identify Krm2 as a regulator of bone remodeling and raise the possibility that antagonizing KRM2 might prove beneficial in patients with bone loss disorders.
authors.affiliation: Institute of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schulze
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seitz
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Saito
authors.forename: Michael
authors.initials: M
authors.lastname: Schneebauer
authors.forename: Robert P
authors.initials: RP
authors.lastname: Marshall
authors.forename: Anke
authors.initials: A
authors.lastname: Baranowsky
authors.forename: Bjoern
authors.initials: B
authors.lastname: Busse
authors.forename: Arndt F
authors.initials: AF
authors.lastname: Schilling
authors.forename: Felix W
authors.initials: FW
authors.lastname: Friedrich
authors.forename: Joachim
authors.initials: J
authors.lastname: Albers
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Spiro
authors.forename: Jozef
authors.initials: J
authors.lastname: Zustin
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Kristina
authors.initials: K
authors.lastname: Ellwanger
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000473:pathology; D010012:Osteogenesis; D010024:Osteoporosis / Q000209:etiology; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; C501127:Dkk1 protein, mouse; C486077:Kremen1 protein, mouse; C558680:Kremen-2 protein, mouse