Osteoblast-specific expression of insulin-like growth factor-1 in bone of transgenic mice induces insulin-like growth factor binding protein-5

Rutter, Meilan M.; Markoff, Edith; Clayton, Lisa M; Akeno, Nagako; Zhao, Guisheng; Clemens, Thomas L.; Chernausek, Steven D.

doi:10.1016/j.bone.2004.10.005

Cited by 18 publications

(12 citation statements)

References 46 publications

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“…In some cell models, it has been demonstrated that IGF-I treatment increases IGFBP-5 mRNA levels [43,44]. In addition, IGF-I treatment also modulates proteolysis of IGFBP-5 in osteoblast cell culture media [45,46], which is suggested by the increased expression of ADAM-9 in the current model.…”

Section: Coordinated Expression Of Igfbp-5 Fhl-2 and Adam-9 In Respmentioning

confidence: 59%

“…Thus, the effect of IGF-I treatment on IGFBP-5 protein level is regulated by both transcriptional and post-transcriptional mechanisms. In this regard, Rutter et al [44] found that IGFBP-5 protein level increased 4-fold in the bones of transgenic mice overexpressing IGF-I in osteoblasts. However, the IGFBP-5 mRNA level was increased only 1.5-fold.…”

Section: Coordinated Expression Of Igfbp-5 Fhl-2 and Adam-9 In Respmentioning

confidence: 99%

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Regulation of insulin-like growth factor binding protein-5, four and a half lim-2, and a disintegrin and metalloprotease-9 expression in osteoblasts

Govoni

Amaar

Kramer

et al. 2006

Growth Hormone & IGF Research

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The roles of insulin-like growth factors (IGFs) in regulating growth and their modulation by six IGF binding proteins (IGFBP) are well established. IGFBP-5, the most abundant IGFBP stored in bone, is an important regulator of bone formation via IGF-dependent and -independent mechanisms. Two new proteins, four and a half lim (FHL)-2, a transcription modulator that interacts with IGFBP-5, and a disintegrin and metalloprotease (ADAM)-9, an IGFBP-5 protease, have been identified as potential regulators of IGFBP-5 action in bone. We tested the hypothesis that agents which modulate bone formation by regulating IGFBP-5 expression would also regulate FHL-2 and ADAM-9 expression in a coordinated manner. We evaluated the expression of IGFBP-5, FHL-2, and ADAM-9 by real-time reverse transcriptase (RT)-PCR during differentiation of mouse bone marrow stromal cells into osteoblasts and in response to treatment with bone formation modulators in the LSaOS human osteosarcoma cell line. IGFBP-5 and FHL-2 increased 4.3-and 3.0-fold (P ≤ 0.01), respectively, during osteoblast differentiation. Dexamethasone (Dex), an inhibitor of bone formation, decreased IGFBP-5 and FHL-2 and increased ADAM-9 in LSaOS cells (P ≤ 0.05). Bone morphogenic protein (BMP)-7, a stimulator of bone formation, increased IGFBP-5 and decreased ADAM-9 (P < 0.01). To determine if BMP-7 would eliminate Dex inhibition of IGFBP-5, cells were treated with Dex + BMP-7. The BMP-7-induced increase in IGFBP-5 was reduced, but not eliminated, in the presence of Dex (P ≤ 0.01), indicating that BMP-7 and Dex may regulate IGFBP-5 via different mechanisms. Transforming growth factor (TGF)-β, a stimulator of bone formation, increased IGFBP-5 and FHL-2 expression (P ≤ 0.01). IGF-I and TNF-α decreased expression of ADAM-9 (P < 0.05). In conclusion, our findings are consistent with the hypothesis that FHL-2 and ADAM-9 are important modulators of IGFBP-5 actions and are, in part, regulated in a coordinated manner in bone.

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Section: Coordinated Expression Of Igfbp-5 Fhl-2 and Adam-9 In Respmentioning

confidence: 59%

Section: Coordinated Expression Of Igfbp-5 Fhl-2 and Adam-9 In Respmentioning

confidence: 99%

Regulation of insulin-like growth factor binding protein-5, four and a half lim-2, and a disintegrin and metalloprotease-9 expression in osteoblasts

Govoni

Amaar

Kramer

et al. 2006

Growth Hormone & IGF Research

View full text Add to dashboard Cite

show abstract

“…Past studies using transgenic mouse models lacking IGF-I or overexpressing IGF-I have shown that IGF-I influences bone accretion by regulating longitudinal growth, bone width, and material bone density (3,18,31,32,42,46,49,53,54). However, the question of whether endocrine or local sources of IGF-I play a predominant role in regulating one or more of the above processes remains to be determined.…”

mentioning

confidence: 99%

Disruption of insulin-like growth factor-I expression in type IIαI collagen-expressing cells reduces bone length and width in mice

Govoni

Lee

Chung

et al. 2007

Physiological Genomics

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S. Disruption of insulin-like growth factor-I expression in type II␣I collagen-expressing cells reduces bone length and width in mice. Physiol Genomics 30: 354-362, 2007. First published May 22, 2007 doi:10.1152/physiolgenomics.00022.2007.-It is well established that insulin-like growth factor (IGF)-I is critical for the regulation of peak bone mineral density (BMD) and bone width. However, the role of systemic vs. local IGF-I is not well understood. To determine the role local IGF-I plays in regulating BMD and bone width, we crossed IGF-I flox/flox mice with procollagen, typeII␣I-Cre mice to generate conditional mutants in which chondrocyte-derived IGF-I was disrupted. Bone parameters were measured by dual X-ray absorptiometry at 2, 4, 8, and 12 wk of age and peripheral quantitative computed tomography at 12 wk of age. Body length, areal BMD, and bone mineral content (BMC) were reduced (P Ͻ 0.05) between 4 and 12 wk in the conditional mutant mice. Bone width was reduced 7% in the vertebrae and femur (P Ͻ 0.05) of conditional mutant mice at 12 wk. Gains in body length and total body BMC and BMD were reduced by 27, 22, and 18%, respectively (P Ͻ 0.05) in conditional mutant mice between 2 and 4 wk of age. Expression of parathyroid hormone related protein, parathyroid hormone receptor, distal-less homeobox (Dlx)-5, SRY-box containing gene-9, and IGF binding protein (IGFBP)-5 were reduced 27, 36, 45, 33, and 45%, respectively, in the conditional mutant cartilage (P Ͻ 0.05); however, no changes in Indian hedgehog, Dlx-3, growth hormone receptor, IGF-I receptor, and IGFBP-3 expression were observed (P Ն 0.20). In conclusion, IGF-I from cells expressing procollagen type II␣I regulates bone accretion that occurs during postnatal growth period. conditional knockout; cre-loxP; postnatal growth; transgenic mice

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“…In addition, this deficiency in bone volume could owe to other components of the GH/IGF-1 system, namely, IGF binding proteins (IGFBP). For example, IGFBP5 levels increased dramatically at three weeks of age in the IGF-1 over-expressing mice mentioned above, coincident with the increase in osteoblast function (45). However, IGFBP5 levels decreased by six weeks of age, in both wild type and transgenic mice, when osteoblast activity had returned to normal in the IGF-1 overexpressing mice; presenting the possibility that reduced matrix-bound IGFBP5 might diminish the capacity of IGF-1 to stimulate bone formation in older animals (45), since matrix-bound IGFBP5 has been shown to potentiate IGF signaling (46,47).…”

Section: Discussionmentioning

confidence: 84%

Osteoblast-restricted Disruption of the Growth Hormone Receptor in Mice Results in Sexually Dimorphic Skeletal Phenotypes

et al. 2013

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Growth hormone (GH) exerts profound anabolic actions during postnatal skeletal development, in part, through stimulating the production of insulin-like growth factor-1 (IGF-1) in liver and skeletal tissues. To examine the requirement for the GH receptor (GHR) in osteoblast function in bone, we used Cre-LoxP methods to disrupt the GHR from osteoblasts, both in vitro and in vivo. Disruption of GHR from primary calvarial osteoblasts in vitro abolished GH-induced signaling, as assessed by JAK2/STAT5 phosphorylation, and abrogated GH-induced proliferative and anti-apoptotic actions. Osteoblasts lacking GHR exhibited reduced IGF-1-induced Erk and Akt phosphorylation and attenuated IGF-1-induced proliferation and anti-apoptotic action. In addition, differentiation was modestly impaired in osteoblasts lacking GHR, as demonstrated by reduced alkaline phosphatase staining and calcium deposition. In order to determine the requirement for the GHR in bone in vivo, we generated mice lacking the GHR specifically in osteoblasts (ΔGHR), which were born at the expected Mendelian frequency, had a normal life span and were of normal size. Three week-old, female ∆GHR mice had significantly reduced osteoblast numbers, consistent with the in vitro data. By six weeks of age however, female ΔGHR mice demonstrated a marked increase in osteoblasts, although mineralization was impaired; a phenotype similar to that observed previously in mice lacking IGF-1R specifically in osteoblasts. The most striking phenotype occurred in male mice however, where disruption of the GHR from osteoblasts resulted in a "feminization" of bone geometry in 16 week-old mice, as observed by μCT. These results demonstrate that the GHR is required for normal postnatal bone development in both sexes. GH appears to serve a primary function in modulating local IGF-1 action. However, the changes in bone geometry observed in male ΔGHR mice suggest that, in addition to facilitating IGF-1 action, GH may function to a greater extent than previously appreciated in establishing the sexual dimorphism of the skeleton. Keywords: growth hormone; osteoblasts; knockout mice; bone; sexual dimorphism coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. During postnatal development, the activity and lifespan of osteoblasts is regulated by many local growth factors, cytokines, and systemic hormones (1,2). Among these, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exert anabolic activity, particularly during the rapid phases of bone acquisition that occur during the pubertal growth [22][23][24].In many tissues, GH actions are mediated by its ability to stimulate the production of IGF-1, a widely expressed polypeptide that bears homology to pro-insulin. IGF-1 signals primarily via the heterotetrameric type-1 IGF-1 receptor (IGF-1R) to trigger ERK and PI3K/Akt activation via SHC and insulin receptor substrate-1 and -2 (IRS-1/2) (25,26). IGF-1 is an important growth and survival factor for many cell types, including osteoblasts (27,28). IGF-1 ...

show abstract

Osteoblast-specific expression of insulin-like growth factor-1 in bone of transgenic mice induces insulin-like growth factor binding protein-5

Cited by 18 publications

References 46 publications

Regulation of insulin-like growth factor binding protein-5, four and a half lim-2, and a disintegrin and metalloprotease-9 expression in osteoblasts

Regulation of insulin-like growth factor binding protein-5, four and a half lim-2, and a disintegrin and metalloprotease-9 expression in osteoblasts

Disruption of insulin-like growth factor-I expression in type IIαI collagen-expressing cells reduces bone length and width in mice

Osteoblast-restricted Disruption of the Growth Hormone Receptor in Mice Results in Sexually Dimorphic Skeletal Phenotypes

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