Insulin‐Like Growth Factor I Is Required for the Anabolic Actions of Parathyroid Hormone on Mouse Bone

Bikle, Daniel D.; Sakata, Toshiie; Leary, Colin; Elalieh, Hashem; Ginzinger, David G.; Rosen, Clifford J.; Beamer, Wesley G.; Majumdar, Sharmila; Halloran, Bernard P.

doi:10.1359/jbmr.2002.17.9.1570

Cited by 245 publications

(201 citation statements)

References 37 publications

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“…Consistent with a role of IGF-I in the anabolic effects of intermittent PTH, daily hormone injections for 14 days to IGF-I null mice failed to stimulate periosteal bone formation or to increase cortical thickness at the tibiofibular junction, whereas wild type mice exhibited the expected anabolic response [88]. For reasons that are unclear, intermittent PTH caused loss of cancellous bone in proximal tibia in wild type mice in this experiment, but this response did not occur in the IGF-I null mice.…”

Section: Igf-imentioning

confidence: 60%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

623

531

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Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of antiapoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPARγ may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

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Section: Igf-imentioning

confidence: 60%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

623

531

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“…31 In the absence of IGF-1 (global-or osteoblast-specific deletion), PTH did not have a positive effect on the rate of bone formation. 42 In addition, it appears that PTH also needs IRS1 and not IRS2 for it to have the full anabolic effect on bone. Because PTH is a therapeutic option for osteoporosis, understanding the principal mechanisms that are operative via the IGF signaling pathways remains a major priority.…”

Section: Igf-1 and Osteoblastsmentioning

confidence: 99%

IGF-1 regulation of key signaling pathways in bone

2013

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Insulin-like growth factor 1 (IGF-1) is an unique peptide that functions in an endocrine/paracrine and autocrine manner in most tissues. Although it was postulated initially that liver-derived IGF-1 was the major source of IGF-1 (that is, the somatomedin hypothesis), it is also produced in a wide variety of tissues and can function in numerous ways as both a proliferative and differentiative factor. One such tissue is bone and all cell lineages in the skeleton have been shown to not only require IGF-1 for normal development and function but also to respond to IGF-1 via the IGF-1 receptor. Ligandreceptor activation leads to several distinct downstream signaling cascades, which have significant implications for cell survival, protein synthesis and energy utilization. The novel role of IGF-1 in regulating metabolic demands of the bone remodeling unit is currently under investigation. More studies are likely to shed new light on various aspects of skeletal physiology and potentially may lead to new therapeutics.

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“…A high dose of ZA (3μg/mouse/day) was based on a dose specified in a previous publication [17] and was chosen to ensure that a maximal response would be observed in the bone regeneration model and thus, the effects of ZA on cell numbers could be effectively evaluated. The dose of PTH (1-34) (40μg/kg/day) used in these studies is within the range of anabolic doses commonly used in mouse experiments [2,18]. The average weight of mice in each treatment group was 30g.…”

Section: In Vivo Treatment Regimensmentioning

confidence: 99%

“…Several mechanisms have been proposed for PTH anabolic actions, including cAMP activation [1], growth factors such as IGF-1 [2], transcriptional mediators in bone such as c-Fos [3] and Runx2 [4], and inhibition of apoptosis [5]. Although it has been suggested that PTH exerts anabolic actions in bone by reducing osteoblast apoptosis in mice, clinically it has been shown that PTH-mediated bone formation is associated with an increase in osteoblast apoptosis [6].…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Pettway

Meganck

Koh

et al. 2008

Bone

107

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PTH (1-34) is the only FDA-approved anabolic agent for osteoporosis treatment in the U.S., but its mechanisms are not completely understood. This study investigated PTH effects on osteogenic cells at various stages of differentiation and proliferation using an engineered bone growth model in vivo. Ossicles were generated from bone marrow stromal cells (BMSCs) implanted in immunocompromised mice. Three weeks of PTH (40μg/kg/d) or vehicle treatment initiated 1 day, 1, 2, or 3wks after BMSC implantation resulted in an anabolic response in PTH-treated implants (via histomorphometry and microCT) in all treatment groups. A novel in vivo tracking strategy with luciferase tagged BMSCs and weekly bioluminescent imaging of ossicles revealed increased donor cell proliferation in PTH-treated ossicles. The greatest increase occurred during the first week, and the activity remained elevated in PTH-treated implants over time. Zoledronic acid (ZA) was combined with PTH to delineate interactive mechanisms of these bone active agents. Combining ZA with PTH treatment reduced the PTH-mediated increase in luciferase BMSC activity, serum osteocalcin, and serum tartrate resistant acid phosphotase-5b (TRAP-5b) but ZA did not reduce the PTH-induced increase in total bone. Since zoledronic acid reduced PTH-induced proliferation without reducing bone volume, these data suggests that combining PTH and bisphosphonate therapy warrants further investigation in the treatment of bone disorders.

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Insulin‐Like Growth Factor I Is Required for the Anabolic Actions of Parathyroid Hormone on Mouse Bone

Cited by 245 publications

References 37 publications

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

IGF-1 regulation of key signaling pathways in bone

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

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