Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone.
Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.
Bikle
Daniel D
DD
Department of Medicine, Veterans Affairs Medical Center and University of California, San Francisco 94121, USA.
Sakata
Takeshi
T
Leary
Colin
C
Elalieh
Hashem
H
Ginzinger
David
D
Rosen
Clifford J
CJ
Beamer
Wesley
W
Majumdar
Sharmila
S
Halloran
Bernard P
BP
D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects; D003094:Collagen / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics; D018016:Receptors, Parathyroid Hormone / Q000235:genetics
D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018016:Receptors, Parathyroid Hormone; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D017526:Receptor, IGF Type 1; D000469:Alkaline Phosphatase