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.
Highlights
Bone is constantly remodelled through the activities of boneforming osteoblasts and bone-resorbing osteoclasts [1,2]
Using immunohistochemistry on human bone sections we found that KRM2 is present in osteoblasts, but not in cells of the bone marrow, albeit we observed a weak staining of bone-resorbing osteoclasts (Figure 1C)
Using DNA-transfection we observed that Dkk1 and Krm2 antagonize the activation of a Wnt-responsive Luciferase reporter gene, only when Wnt1 or Wnt3 expression plasmids are co-transfected, but that Luciferase expression is increased by Krm2, when a Wnt2 expression plasmid is used instead (Figure 1C)
Summary
Bone is constantly remodelled through the activities of boneforming osteoblasts and bone-resorbing osteoclasts [1,2]. A relative increase of bone resorption over bone formation can result in osteoporosis, one of the most prevalent diseases in the aged population [3,4] It is of hallmark clinical importance to identify molecules regulating the differentiation and activity of osteoblasts, since these can potentially serve as targets for osteoanabolic therapy. As these molecules should be accessible to drugs, they should ideally be located in the extracellular space or at the cell surface, for instance as a receptor for a given ligand. Based on this cumulative evidence, and due to its transmembrane localization, LRP5 has been considered an excellent target molecule for osteoanabolic therapy
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