Although it has been established that PTH exerts potent anabolic effects on
bone in animals and humans, the mechanism of PTH action on bone remains co
ntroversial. Based on the previous findings that PTH treatment increased pr
oduction of IGF-I in bone cells and that PTH effects on bone cells in vitro
were blocked by IGF-I-blocking antibodies, we proposed that IGF-I action i
s required for the stimulatory effects of PTH on bone formation. To test th
is hypothesis, we evaluated the effects of PTH on bone formation parameters
in growing mice lacking functional IGF-I genes. Five-week-old IGF-I(-/-) m
ice and wild-type littermates were given daily se injections of 160 mug/kg
body weight of PTH (1-34) or vehicle for 10 d. In wildtype animals, PTH cau
sed a significant increase in serum osteocalcin levels (113%), serum alkali
ne phosphatase activity (48%), and alkaline phosphatase activity in femoral
bone ex-tracts (> 80%), compared with the vehicle-treated control group. I
n contrast, in IGF-I(-/-) mice, there was no significant effect of PTH on a
ny bone formation parameters. PTH treatment increased total bone mineral de
nsity, as evaluated by peripheral quantitative computer tomography, at the
distal metaphysis of the femur by 40% in wild-type mice, but it had no effe
ct on bone mineral density in mice lacking functional IGF-I genes. In vitro
studies using osteoblasts derived from control and IGF-I(-/-) mice reveale
d that PTH treatment increased cell number in osteoblasts derived from IGF-
I knockout mice in the presence of exogenously added IGF-I but not without
IGF-I. These data to our knowledge provide the first direct evidence that t
he anabolic effects of PTH on bone formation in vivo require IGF-I action i
n growing mice.