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Title:   Author  item
                                            Cao, Jayitem
                                            KURIMOTO, PAMELA - UNIV CALIF - SAN FRANCISCitem
                                            BOUDIGNON, BENJAMIN - UNIV CALIF - SAN FRANCISCitem
                                            ROSEN, CLIFFORD - MAIN CTR FOR OSTEOPOROSISitem
                                            LIMA, FLORENCE - UNIV CALIF - SAN FRANCISCitem
                                            HALLORAN, BERNARD - UNIV CALIF - SAN FRANCISC
  Submitted to: Journal of Bone and Mineral Research
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 5/2/2007
                                    Publication  Date: 5/7/2007
                                    Citation: Cao, J.J., Kurimoto, P., Boudignon, B., Rosen, C., Lima, F., Halloran, B.P. 2007. Aging impairs IGF-1 receptor activation and induces skeletal resistance to IGF-1. Journal of Bone and Mineral Research. 22(8):1271-1279.Interpretive Summary: Insulin-like growth factor (IGF-I) is a potent anabolic agent for bone. It increases the number and proliferation of bone forming cells, osteoblasts, and therefore stimulates bone formation and maintains bone mass. With aging, bone mass and strength decrease and bone becomes resistant to the anabolic actions of IGF-I. To investigate the mechanism of decreased bone responsiveness to IGF-I with aging, we measured the pro-proliferative, anti-apoptotic and functional responses of bone and bone marrow stromal cells to IGF-I, and evaluated IGF-I signal transduction in different ages of mice. After treatment with IGF-1 for two weeks, we measured osteoblast proliferation in cell culture and bones of male C57BL/6 mice 6 weeks, 6 months and 24 months. We also measured bone formation markers in vitro and IGF-I signaling elements and their activation in IGF-I treated cells. Our data show that aging is accompanied by alterations in IGF-I signaling that involve receptor activation. Faulty receptor activation is likely responsible for impaired downstream signaling. The effect of these changes is to reduce responsiveness to IGF-I and decrease bone formation. Our finding on the changes in signaling pathway with aging provides an opportunity in the prevention or treatment of osteoporosis which affects millions of Americans.
                                Technical Abstract: Insulin-like growth factor (IGF-I) plays an important anabolic role in stimulating bone formation and maintaining bone mass. We show that the pro-proliferative, anti-apoptotic and functional responses to IGF-I in bone and BMSC decrease with aging. These changes are associated with impaired receptor activation and signal transduction through the MAPK and PI3K pathways. 
Introduction: Insulin-like growth factor (IGF-I) is a potent anabolic agent having effects across diverse tissues and cell types. With aging, bone becomes resistant to the anabolic actions of IGF-I. To examine the effects of aging on bone responsiveness to IGF-I, we measured the pro-proliferative, anti-apoptotic and functional responses of bone and BMSCs to IGF-I, and evaluated IGF-I signal transduction in young, adult and old mice. 
Materials and Methods: Male C57BL/6 mice 6 weeks (young), 6 months (adult) and 24 months (old) were treated with IGF-I for two weeks using osmotic minipumps, and osteoblast proliferation (BrdU labeling) in vivo and osteoprogenitor number (BMSC culture and calcium nodule formation) were measured. Proliferation, apoptosis and expression of key osteoblast factors (alkaline phosphatase, collagen, osteocalcin, RANKL, OPG, M-CSF), and IGF-I signaling elements and their activation in IGF-I treated cells were studied using QRT-PCR and Western blot analysis. Data were analyzed using ANOVA. 
Results: Aging decreased the basal and IGF-I stimulated number of BrdU labeled osteoblasts, and reduced the ability of IGF-I to stimulate osteoprogenitor 3 formation (calcium nodule number) by 50%. The pro-proliferative and anti-apoptotic actions of IGF-I were blunted in cells from old animals. These changes were accompanied by age-related alterations in the ability of IGF-I to regulate alkaline phosphatase, collagen, osteocalcin, RANKL, OPG and M-CSF expression. IGF-I binding was normal but IGF-I receptor mRNA and protein expression was increased in aged animals by 2 and 10 fold, respectively. The age-related changes in proliferation, apoptosis and function were accompanied by loss of IGF-I-induced signaling at the receptor level and at key regulatory sites along the MAPK (ERK1/2) and PI3K (AKT) pathways. 
Conclusions: Our data show that aging is accompanied by loss of bone and BMSC/osteoblast responsiveness to IGF-I, and that these changes are associated with resistance to IGF-I signaling that involve receptor activation and down stream signaling events.


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