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Abstract
Secreted frizzled-related protein 1 (sFRP1) is an antagonist of Wnt signaling, an important pathway in maintaining bone homeostasis. In this study we evaluated the skeletal phenotype of mice overexpressing sFRP1 (sFRP1 Tg) and the interaction of parathyroid hormone (PTH) treatment and sFRP1 (over)expression. Bone mass and microarchitecture were measured by micro-computed tomography (µCT). 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 sFRP1 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 sFRP1 Tg mice of both sexes. Bone resorption was similar between sFRP1 Tg and WT females and was higher in sFRP1 Tg male mice. Treatment with hPTH(1-34) (40 µg/kg/d) for 2 weeks increased trabecular bone volume in WT mice (females: +30% to 50%; males: +35% to 150%) compared with sFRP1 Tg mice (females: +5%; males: +18% to 54%). Percentage increases in bone formation also were lower in PTH-treated sFRP1 Tg mice compared with PTH-treated WT mice. In conclusion, overexpression of sFRP1 inhibited bone formation as well as attenuated PTH anabolic action on bone. The gender differences in the bone phenotype of the sFRP1 Tg animal warrants further investigation. © 2010 American Society for Bone and Mineral Research
Highlights
The wingless and Int1 (Wnt) family of secreted proteins regulates many aspects of cell growth, differentiation, and death during both embryogenesis and adult life.[1]
The Secreted frizzled-related protein 1 (sFRP1) Tg mice used for this research project, STOCK Tg(sFRP1-EGFP)142Gsat/Mmcd and identification number 011017-UCD, were obtained from the Mutant Mouse Regional Resource Center (MMRRC), a National Center for Research Resource (NCRR)-National Institutes of Health (NIH)–funded strain repository and were donated to the MMRRC by the National Institute of Neurological Disorders and Stroke (NINDS)funded Gene Expression Nervous System ATLas (GENSAT) engineering bacterial artificial chromosomes (BAC) transgenic project
This study determined that overexpression of sFRP1 in mice results in an osteopenic phenotype characterized by an inhibition of bone formation, with males being more severely affected than females
Summary
The wingless and Int (Wnt) family of secreted proteins regulates many aspects of cell growth, differentiation, and death during both embryogenesis and adult life.[1]. During in vivo bone development, Wnt/b-catenin signaling prevents MSCs from differentiating into chondrocytes[6] and promotes osteoblast differentiation.[7] b-Catenin signaling in differentiated osteoblasts has been shown to negatively control osteoclast formation and bone resorption through an increase in osteoprotegerin production by osteoblasts.[8] Similar to other growth factors, Wnt signaling can be antagonized by secreted or intracellular inhibitors. The sFRPs antagonize Wnt function by binding to the Wnt proteins and preventing Wnt/ receptor activation. Since Wnt signaling is critical for osteoblast maturation, skeletal acquisition, and maintenance, we hypothesized that overexpression of sFRP1 in sFRP1 transgenic mice (sFRP1 Tg) would reduce osteoblast number and activity such that these animals would have lower peak bone mass and reduced bone acquisition. We were interested in the effect of PTH treatment in sFRP1 Tg mice
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