The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice
Department of Cell Biology
Medical Subject Headings
Animals; Apoptosis; Bone Density; Female; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Knockout; Osteoblasts; Osteogenesis; Protein Binding; Proteins; RNA, Messenger; Signal Transduction; Tissue Distribution; Wnt Proteins
Previous studies have associated activation of canonical Wnt signaling in osteoblasts with elevated bone formation. Here we report that deletion of the murine Wnt antagonist, secreted frizzled-related protein (sFRP)-1, prolongs and enhances trabecular bone accrual in adult animals. sFRP-1 mRNA was expressed in bones and other tissues of +/+ mice but was not observed in -/- animals. Despite its broad tissue distribution, ablation of sFRP-1 did not affect blood and urine chemistries, most nonskeletal organs, or cortical bone. However, sFRP-1-/- mice exhibited increased trabecular bone mineral density, volume, and mineral apposition rate when compared with +/+ controls. The heightened trabecular bone mass of sFRP-1-/- mice was observed in adult animals between the ages of 13-52 wk, occurred in multiple skeletal sites, and was seen in both sexes. Mechanistically, loss of sFRP-1 reduced osteoblast and osteocyte apoptosis in vivo. In addition, deletion of sFRP-1 inhibited osteoblast lineage cell apoptosis while enhancing the proliferation and differentiation of these cells in vitro. Ablation of sFRP-1 also increased osteoclastogenesis in vitro, although changes in bone resorption were not observed in intact animals in vivo. Our findings demonstrate that deletion of sFRP-1 preferentially activates Wnt signaling in osteoblasts, leading to enhanced trabecular bone formation in adults.
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Citation: Mol Endocrinol. 2004 May;18(5):1222-37. Epub 2004 Feb 19. Link to article on publisher's site