verexpression of Secreted Frizzled-Related Protein 1 Inhibits Bone Formation and Attenuates Parathyroid Hormone Bone Anabolic Effects

摘要

Secreted frizzled-related protein 1 (sFRPI) is an antagonist of Wnt signaling, an important pathway in maintaining bone homeostasis. In this study we evaluated the skeletal phenotype of mice overexpressing sFRPI (sFRPI Tg) and the interaction of parathyroid hormone (PTH) treatment and sFRPI (over)expression. Bone mass and microarchitecture were measured by micro-computed tomography i^CT). Osteoblastic and osteoclastic cell maturation and function were assessed in primary bone marrow cell cultures. Bone turnover was assessed by biochemical markers and dynamic bone histomorphometry. Real-time PCR was used to monitor the expression of several genes that regulate osteoblast maturation and function in whole bone. We found that trabecular bone mass measurements in distal femurs and lumbar vertebral bodies were 22% and 51% lower in female and 9% and 33% lower in male sFRPI Tg mice, respectively, compared with wild-type (WT) controls at 3 months of age. Genes associated with osteoblast maturation and function, serum bone formation markers, and surface based bone formation were significantly decreased in sFRPI Tg mice of both sexes. Bone resorption was similar between sFRPI Tg and WT females and was higher in sFRPI Tg male mice. Treatment with hPTH(1-34) (40 mug/kg/d) for 2 weeks increased trabecular bone volume in WT mice (females: +30% to 50%; males: +35% to 150%) compared with sFRPI Tg mice (females: +5%; males: +18% to 54%). Percentage increases in bone formation also were lower in PTH-treated sFRPI Tg mice compared with PTH-treated WT mice. In conclusion, overexpression of sFRPI inhibited bone formation as well as attenuated PTH anabolic action on bone. The gender differences in the bone phenotype of the sFRPI Tg animal warrants further investigation. and Mineral Research.