The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice
Department of Cell Biology
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.
DOI of Published Version
Mol Endocrinol. 2004 May;18(5):1222-37. Epub 2004 Feb 19. Link to article on publisher's site
Molecular endocrinology (Baltimore, Md.)
Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert A, Goad M, Gaur T, Stein GS, Lian JB, Komm BS. (2004). The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Stein, Stein, Lian, vanWijnen Lab Publications. https://doi.org/10.1210/me.2003-0498. Retrieved from https://escholarship.umassmed.edu/stein/57