Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2.
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Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2. / Schulze, Jochen; Seitz, Sebastian; Saito, Hiroaki; Schneebauer, Michael; Marshall, Robert-Percy; Baranowsky, Anke; Busse, Björn; Schilling, Arndt; Friedrich, Felix; Albers, Joachim; Spiro, Alexander Simon; Zustin, Jozef; Streichert, Thomas; Ellwanger, Kristina; Niehrs, Christof; Amling, Michael; Baron, Roland; Schinke, Thorsten.
in: PLOS ONE, Jahrgang 5, Nr. 4, 4, 2010, S. 10309.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2.
AU - Schulze, Jochen
AU - Seitz, Sebastian
AU - Saito, Hiroaki
AU - Schneebauer, Michael
AU - Marshall, Robert-Percy
AU - Baranowsky, Anke
AU - Busse, Björn
AU - Schilling, Arndt
AU - Friedrich, Felix
AU - Albers, Joachim
AU - Spiro, Alexander Simon
AU - Zustin, Jozef
AU - Streichert, Thomas
AU - Ellwanger, Kristina
AU - Niehrs, Christof
AU - Amling, Michael
AU - Baron, Roland
AU - Schinke, Thorsten
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0010309
DO - 10.1371/journal.pone.0010309
M3 - SCORING: Zeitschriftenaufsatz
VL - 5
SP - 10309
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 4
M1 - 4
ER -