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Updated: Jul 11, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass
Rika Nakanishi1, Haruhiko Akiyama, Hiroaki Kimura
1Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Unlabelled:
Transgenic mice overexpressing Sfrp4 in osteoblasts were established. These mice exhibited low bone mass caused by a decrease in bone formation.
Introduction:
We recently reported that single nucleotide polymorphisms in the secreted frizzled-related protein 4 (Sfrp4) gene are responsible for low peak BMD in senescence-accelerated mouse (SAM) P6. In vitro studies revealed inhibition of osteoblast proliferation by Sfrp4, which is supposed to be mediated by canonical Wnt signaling.
Materials And Methods:
We examined the expression of Sfrp4 in neonate long bones by in situ hybridization and generated transgenic mice in which Sfrp4 was specifically overexpressed in osteoblasts under the control of a 2.3-kb Col1a1 osteoblast-specific promoter. Next, we compared the phenotype of Sfrp4 transgenic (Sfrp4 TG) mice with that of mice in which one allele of beta-catenin was conditionally disrupted in osteoblasts (betaChet), and administered lithium chloride (LiCl) to Sfrp4 TG mice.
Results:
Hemizygous Sfrp4 TG mice exhibited a 30% reduction of trabecular bone mass compared with that in wildtype littermates at 8 wk of age, and histomorphometrical analysis showed decreases in both osteoblast numbers and bone formation rate. betaChet mice exhibited a 17% reduction of trabecular bone mass in distal femora caused by an increase in the osteoclast number and a decrease in bone formation rate. Furthermore, LiCl administration rescued the bone phenotype of Sfrp4 TG mice.
Conclusions:
Expression of Sfrp4 in periosteum and bone tissues suggested the role of Sfrp4 in osteoblasts, and we identified that overexpression of Sfrp4 in osteoblasts suppressed osteoblast proliferation, resulting in a decrease in bone formation in vivo. Partial suppression of beta-catenin/canonical Wnt signaling also impaired bone formation, and activation of the signaling restored low bone mass of Sfrp4 TG mice. Thus, these results indicate that Sfrp4 decreases bone formation at least in part by attenuating canonical Wnt signaling in vivo.
Insights
Overexpressing secreted frizzled-related protein 4 (Sfrp4) in osteoblasts reduces bone mass by decreasing bone formation. Activating Wnt signaling rescued this low bone mass phenotype, indicating Sfrp4
Area of Science:
- Bone biology
- Genetics
- Endocrinology
Background:
- Single nucleotide polymorphisms in secreted frizzled-related protein 4 (Sfrp4) are linked to low peak bone mineral density (BMD).
- In vitro studies suggest Sfrp4 inhibits osteoblast proliferation via canonical Wnt signaling.
Purpose of the Study:
- To investigate the in vivo role of Sfrp4 in bone formation.
- To determine the mechanism by which Sfrp4 affects bone mass.
Main Methods:
- Generated transgenic mice overexpressing Sfrp4 in osteoblasts.
- Analyzed bone phenotype and bone formation parameters.
- Administered lithium chloride (LiCl) to rescue the phenotype.
Main Results:
- Sfrp4 transgenic mice showed a 30% reduction in trabecular bone mass due to decreased osteoblast numbers and bone formation rate.
- Lithium chloride administration restored bone mass in Sfrp4 transgenic mice.
- Comparison with beta-catenin conditional knockout mice highlighted distinct mechanisms affecting bone mass.
Conclusions:
- Osteoblast-specific Sfrp4 overexpression suppresses osteoblast proliferation and bone formation in vivo.
- Sfrp4 reduces bone formation partly by attenuating canonical Wnt signaling.
- Wnt signaling modulation offers a potential therapeutic strategy for Sfrp4-related bone loss.
