Transgenic mice overexpressing secreted frizzled-related proteins (sFRP)4 under the control of serum amyloid P promoter exhibit low bone mass but did not result in disturbed phosphate homeostasis.
Secreted frizzled-related protein-4 (sFRP4) is a member of secreted modulators of Wnt signaling pathways and has been recognized to play important role in the pathogenesis of oncogenic osteomalacia as a potential phosphatonin. To investigate the role of sFRP4 in bone biology and phosphorus homeostasis in postnatal life, we generated transgenic mice that overexpress sFRP4 under the control of the serum amyloid P promoter (SAP-sFRP4), which drives transgene expression postnatally. Serum phosphorus level and urinary phosphorus excretion were slightly lower and higher, respectively, in SAP-sFRP4 compared to wild-type (WT) littermate, but the difference did not reach statistical significance. However, renal Na(+/-)/Pi co-transporter (Npt) 2a and 1alpha-hydroxylase gene expression were up-regulated in SAP-sFRP4 mice. In addition, the level of serum 1,25-dihydroxyvitamin D(3) was higher in SAP-sFRP4 mice. At 5 weeks of age, bone mineral density (BMD) in SAP-sFRP4 was similar to that in WT. However, with advancing age, SAP-sFRP4 mice gained less BMD so that areal BMD of SAP-sFRP4 mice was significantly lower compared to WT at 15 weeks of age. Histomorphometric analysis of proximal tibia showed that trabecular bone volume (BV/TV) and thickness (Tb.Th) were significantly lower in SAP-sFRP4 mice. There was no evidence of osteomalacia in histological analysis. Our data do not support the role of sFRP4 per se as a phosphatonin but suggest that sFRP4 negatively regulates bone formation without disrupting phosphorus homeostasis.
Cho
Hwa Young
HY
Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Republic of Korea.
Choi
Hyung Jin
HJ
Sun
Hyun Jin
HJ
Yang
Jae-Yeon
JY
An
Jee Hyun
JH
Cho
Sun Wook
SW
Kim
Sang Wan
SW
Kim
Seong Yeon
SY
Kim
Jung Eun
JE
Shin
Chan Soo
CS
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000502:physiology; D015519:Bone Density / Q000502:physiology; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D002469:Cell Separation; D005786:Gene Expression Regulation; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology; D010710:Phosphates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000683:Serum Amyloid P-Component / Q000235:genetics*; D012886:Skull / Q000166:cytology; D000094742:Secreted Frizzled-Related Proteins
D010710:Phosphates; D011518:Proto-Oncogene Proteins; D000683:Serum Amyloid P-Component; C498454:Sfrp4 protein, mouse; D000094742:Secreted Frizzled-Related Proteins