Bone anabolic effects of parathyroid hormone are blunted by deletion of the Wnt antagonist secreted frizzled-related protein-1.
Secreted frizzled-related protein (sFRP)-1 is a Wnt antagonist that when deleted in mice leads to increased trabecular bone formation in adult animals after 13 weeks of age. Treatment of mice with parathyroid hormone (PTH) also increases trabecular bone formation, and some of the anabolic actions of this hormone may result from altered expression of Wnt pathway components. To test this hypothesis, we treated +/+ and -/- female sFRP-1 mice with PTH 1-34 for 30 days and measured distal femur trabecular bone parameters by peripheral quantitative computed tomography (pQCT) and high-resolution micro-computed tomography. During the course of the 32-week study, volumetric bone mineral density (vBMD) declined 41% in vehicle-treated +/+ mice, but increased 24% in vehicle-treated -/- animals. At 8 weeks of age when vBMD was not altered by deletion of sFRP-1, treatment of +/+ and -/- mice with PTH increased vBMD by 147 and 163%, respectively. In contrast, at 24 weeks of age when vBMD was 75% higher in -/- mice than in +/+ controls, treatment with PTH increased vBMD 164% in +/+ animals, but only 58% in -/- mice. Furthermore, at 36 weeks of age when vBMD was 117% higher in -/- mice than in +/+ controls, treatment with PTH increased vBMD 74% in +/+ animals, while no increase was observed in -/- mice. At each of these time points, PTH treatment increased vBMD to a similar level in +/+ and -/- mice, and this level declined with age. In addition, at 36 weeks of age, the vBMD level reached by PTH treatment of +/+ mice was the same as that achieved solely by deletion of sFRP-1. These results indicate that loss of sFRP-1 and PTH treatment increase vBMD to a similar extent. Moreover, as the effects of sFRP-1 deletion on vBMD increase, the ability of PTH to enhance vBMD declines suggesting that there are overlapping mechanisms of action.
Bodine
Peter V N
PV
Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania 19426, USA. bodinep@wyeth.com
Seestaller-Wehr
Laura
L
Kharode
Yogendra P
YP
Bex
Frederick J
FJ
Komm
Barry S
BS
D000375:Aging / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D001846:Bone Development / Q000187:drug effects / Q000235:genetics*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics*; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019379:Teriparatide / Q000031:analogs & derivatives / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D019379:Teriparatide; D051153:Wnt Proteins; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C035748:parathyroid hormone (1-34)amide