IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone.
We showed that the IGF-IR-null mutation in mature osteoblasts leads to less bone and decreased periosteal bone formation and impaired the stimulatory effects of PTH on osteoprogenitor cell proliferation and differentiation.


BACKGROUND
This study was carried out to examine the role of IGF-I signaling in mediating the actions of PTH on bone.


METHODS
Three-month-old mice with an osteoblast-specific IGF-I receptor null mutation (IGF-IR OBKO) and their normal littermates were treated with vehicle or PTH (80 microg/kg body weight/d for 2 wk). Structural measurements of the proximal and midshaft of the tibia were made by microCT. Trabecular and cortical bone formation was measured by bone histomorphometry. Bone marrow stromal cells (BMSCs) were obtained to assess the effects of PTH on osteoprogenitor number and differentiation.


RESULTS
The fat-free weight of bone normalized to body weight (FFW/BW), bone volume (BV/TV), and cortical thickness (C.Th) in both proximal tibia and shaft were all less in the IGF-IR OBKO mice compared with controls. PTH decreased FFW/BW of the proximal tibia more substantially in controls than in IGF-IR OBKO mice. The increase in C.Th after PTH in the proximal tibia was comparable in both control and IGF-IR OBKO mice. Although trabecular and periosteal bone formation was markedly lower in the IGF-IR OBKO mice than in the control mice, endosteal bone formation was comparable in control and IGF-IR OBKO mice. PTH stimulated endosteal bone formation only in the control animals. Compared with BMSCs from control mice, BMSCs from IGF-IR OBKO mice showed equal alkaline phosphatase (ALP)(+) colonies on day 14, but fewer mineralized nodules on day 28. Administration of PTH increased the number of ALP(+) colonies and mineralized nodules on days 14 and 28 in BMSCs from control mice, but not in BMSCs from IGF-IR OBKO mice.


CONCLUSIONS
Our results indicate that the IGF-IR null mutation in mature osteoblasts leads to less bone and decreased bone formation, in part because of the requirement for the IGF-IR in mature osteoblasts to enable PTH to stimulate osteoprogenitor cell proliferation and differentiation.
Wang
Yongmei
Y
Department of Medicine, Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Nishida
Shigeki
S
Boudignon
Benjamin M
BM
Burghardt
Andrew
A
Elalieh
Hashem Z
HZ
Hamilton
Michelle M
MM
Majumdar
Sharmila
S
Halloran
Bernard P
BP
Clemens
Thomas L
TL
Bikle
Daniel D
DD
D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight; D001842:Bone and Bones / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D017931:DNA Primers; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009929:Organ Size; D010281:Parathyroid Hormone / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D015415:Biomarkers; D017931:DNA Primers; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1