Overexpression of secreted frizzled-related protein 1 inhibits bone formation and attenuates parathyroid hormone bone anabolic effects

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

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

“…The observations that mice lacking DKK1 show increased bone formation and bone mass (57) whereas mice overexpressing DKK1 in osteoblasts are osteopenic (58) suggest that pharmacological DKK1 antagonists may increase bone formation and bone mass. sFRP1, another Wnt antagonist that acts by binding Wnt proteins, (59) could also be targeted because overexpression of sFRP1 inhibits bone formation whereas deletion of sFRP1 increases bone mass in mice (60). Oncostatin may also be targeted to promote bone formation because this cytokine produced by osteoblasts and osteocytes promotes bone formation via activation of leukemia inhibitory factor receptor and decreased sclerostin production (61).…”

Fibroblast Growth Factor 2 Stimulation of Osteoblast Differentiation and Bone Formation Is Mediated by Modulation of the Wnt Signaling Pathway

“…The function of the Wnt pathway on bone formation is also regulated by Wnt antagonists including Dickkopfs (Dkks) (27), Sclerostin (28) and secreted Frizzled receptors (sFRP) (29,30). Dkk1 has been demonstrated to antagonize canonical Wnt signaling and inversely correlates with bone mass (31)(32)(33)(34).…”

“…Besides antagonizing canonical Wnt signaling (31), Dkk2 has been demonstrated to have a role in terminal osteoblast differentiation and mineralized matrix formation (35). Sclerostin (36 -38), sFRP1 (29,30), and sFRP4 (39 -41) also negatively regulate bone mass. sFRPs inactivate all of the Wnt pathway (27).…”

Building bone with a SOST-PTH partnership

“…(21)(22)(23) Many of these genes have been identified to play a role in PTH anabolic action in studies of knockout mice, including transcription factors ATF4 (18) and CREM (24) ; signaling molecules such as b-arrestin (25) ; cytokines such as fibroblast growth factor 2 (FGF2), (16) interleukin 18 (IL-18), (15) and insulin-like growth factor 1 (IGF-1) (26) ; matrix proteins including osteonectin (27) ; and other factors that regulate Wnt pathway signaling including secreted Frizzled-related protein 1 (sFRP-1). (28,29) Surprisingly, given the results in SOST transgenic mice, anabolic treatment with PTH was just as effective in the absence of low density lipoprotein receptorrelated protein 5 (LRP5) as in wild-type mice. (30,31) This may indicate that the component of the anabolic effect of PTH that is dependent on sclerostin is not dependent on LRP5.…”