sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss.
sFRP4 is an extracellular Wnt antagonist that fine-tunes its signal activity by direct binding to Wnts. Bone fragility under oxidative stress by diabetes and aging is partly related to the suppression of the Wnt signal through upregulated sFRP4. Here, to explore the functions of sFRP4 as a balancer molecule in bone development and remodeling, we analyzed the sFRP4 knock-in mouse strain. X-gal and immunohistochemically stained signals in sFRP4-LacZ heterozygous mice were detectable in restricted areas, mostly in osteoblasts and osteoclasts, of the femoral diaphysis after neonatal and postnatal stages. Histological and μCT analyses showed increased trabecular bone mass with alteration of the Wnt signal and osteogenic activity in sFRP4 mutants; this augmented the effect of the buildup of trabecular bone during the ageing period. Our results indicate that sFRP4 plays a critical role in bone development and remodeling by regulating osteoblasts and osteoclasts, and that its functional loss prevents age-related bone loss in the trabecular bone area. These findings imply that sFRP4 functions as a key potential endogenous balancer of the Wnt signaling pathway by efficiently having direct influence on both bone formation and bone absorption during skeletal bone development and maintenance through remodeling.
Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan.
Ryuma
R
Haraguchi
Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan.|Department of Diagnostic Pathology, Ehime University Hospital, Shitsukawa, Toon City, Ehime 791-0295, Japan.
Riko
R
Kitazawa
Department of Pathology, National Hospital Organization, Osaka National Hospital, Hoenzaka, Chuo-ku, Osaka City, Osaka 540-0006, Japan.
Kiyoshi
K
Mori
Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan.
Ryosuke
R
Tachibana
Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Minatojima Minami-machi, Chuo-Ku, Kobe City, Hyogo 650-0047, Japan.|Genetic Engineering Team, RIKEN Center for Life Science Technologies, Minatojima Minami-machi, Chuo-Ku, Kobe City, Hyogo 650-0047, Japan.
Hiroshi
H
Kiyonari
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan.
Yuuki
Y
Imai
Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Minatojima Minami-machi, Chuo-Ku, Kobe City, Hyogo 650-0047, Japan.|Genetic Engineering Team, RIKEN Center for Life Science Technologies, Minatojima Minami-machi, Chuo-Ku, Kobe City, Hyogo 650-0047, Japan.
Takaya
T
Abe
Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan.
Sohei
S
Kitazawa
D000818:Animals; D016723:Bone Remodeling; D000071556:Cancellous Bone / Q000254:growth & development* / Q000378:metabolism; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
D011518:Proto-Oncogene Proteins; C498454:Sfrp4 protein, mouse; D000094742:Secreted Frizzled-Related Proteins