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Osteoblast‐Targeted Expression of Sfrp4 in Mice Results in Low Bone Mass
Author(s) -
Nakanishi Rika,
Akiyama Haruhiko,
Kimura Hiroaki,
Otsuki Bungo,
Shimizu Motoyuki,
Tsuboyama Tadao,
Nakamura Takashi
Publication year - 2008
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.071007
Subject(s) - osteoblast , bone mass , medicine , expression (computer science) , endocrinology , biology , osteoporosis , genetics , computer science , programming language , in vitro
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 β‐catenin was conditionally disrupted in osteoblasts (βChet), 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. βChet 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 β‐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.