The Wnt Antagonist Secreted Frizzled-Related Protein-1 Is a Negative Regulator of Trabecular Bone Formation in Adult Mice

TLDR

Activation of canonical Wnt signaling in osteoblasts is known to elevate bone formation. Loss of sFRP‑1 decreases osteoblast and osteocyte apoptosis, promotes osteoblast proliferation and differentiation, and increases osteoclastogenesis in vitro while not altering bone resorption in vivo. Deleting sFRP‑1 in adult mice prolongs and enhances trabecular bone accrual across multiple sites and sexes, raising bone mineral density, volume, and apposition rates without affecting cortical bone or systemic chemistry, thereby demonstrating that sFRP‑1 is a negative regulator of trabecular bone formation via Wnt signaling.

Abstract

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.