IGFBP-4 regulates adult skeletal growth in a sex-specific manner.
Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actionsin vitroYet,in vivostudies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-oldIgfbp4-/-mice. Both male and female adultIgfbp4-/-mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-oldIgfbp4-/-females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-oldIgfbp4-/-females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation inIgfbp4-/-females. In contrast,Igfbp4-/-males had lower mineralized surface/bone surface. Femoral expression ofSostand circulating levels of sclerostin were reduced but only inIgfbp4-/-males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells fromIgfbp4-/-females but decreased in males. In sum, our results indicate that loss ofIgfbp4affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor.
Maine Medical Center Research InstituteScarborough, Maine, USA david.maridas@maine.edu.
David E
DE
Maridas
Maine Medical Center Research InstituteScarborough, Maine, USA.
Victoria E
VE
DeMambro
Maine Medical Center Research InstituteScarborough, Maine, USA.
Phuong T
PT
Le
Harvard School of Dental MedicineBoston, Massachusetts, USA.
Kenichi
K
Nagano
Harvard School of Dental MedicineBoston, Massachusetts, USA.
Roland
R
Baron
VA Loma Linda Healthcare SystemLoma Linda, California, USA.
Subburaman
S
Mohan
Maine Medical Center Research InstituteScarborough, Maine, USA.
Clifford J
CJ
Rosen
D000818:Animals; D001835:Body Weight / Q000502:physiology; D001846:Bone Development / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D005260:Female; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D012727:Sex Characteristics
D018974:Insulin-Like Growth Factor Binding Protein 4
IGF; IGFBP4; bone; gender; mice; phenotype