Isolation of a novel insulin-like growth factor (IGF) binding protein from human bone: A potential candidate for fixing IGF-II in human bone

Bautista, Catalino M.; Baylink, David J.; Mohan, Subburaman

doi:10.1016/s0006-291x(05)80249-9

Cited by 169 publications

(94 citation statements)

References 21 publications

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“…Similar fragments resulting from proteolysis of IGFBP-5 have been reported in follicle stimulating hormone (FSH)-stimulated rat granulosa cells (Fielder et al, 1993) and in seminal plasma (Lee et al, 1994). Bautista et al (1991) have also demonstrated that addition of equimolar concentrations of IGF-II and IGFBP-5 in mouse MC3T3-E1 osteoblast culture resulted in potentiation of IGF-II action.…”

Section: Igfbp-5supporting

confidence: 62%

Biological roles of insulin-like growth factor binding proteins (IGFBPs)

Kim

Rosenfeld²,

Oh³

1997

Exp Mol Med

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The insulin-like growth factor binding protein (IGFBP) family is a critical component of the insulin-like growth factor (IGF) system which regulate the biological actions of the IGFs and may also be capable of IGFindependent actions. To date, seven distinct IGFBPs have been described. Among these IGFBPs, IGFBPs-1-6 bind IGFs with high affinity, while only IGFBP-7 binds with low affinity. Recently, we have demonstrated that connective tissue growth factor (CTGF) also binds IGFs with low affinity, suggesting that a family of low-affinity IGFBPs, distinct from the highaffinity members, may exist, and together these constitute an IGFBP superfamily. IGFBPs have various biological roles. IGFBPs act not only as a carrier proteins, but also as a modulators of IGF actions by involving in IGF ligand-receptor interactions through influences on both the bioavailability and distribution of IGFs in the extracellular environment. In addition, some IGFBPs (IGFBPs-1, -3, and -5) appears to have intrinsic activity independent of IGFs. This review will focus on recent studies on the biological roles of IGFBPs in IGF-dependent and IGF-independent modes.

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Section: Igfbp-5supporting

confidence: 62%

Biological roles of insulin-like growth factor binding proteins (IGFBPs)

Kim

Rosenfeld²,

Oh³

1997

Exp Mol Med

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“…Studies on the relative distribution of growth factors in humans revealed that bone contains many more IGFs than any of the growth factor systems tested to date. Our studies on the mechanism by which IGFs are fixed in such large quantities led to the finding that they are fixed in bone via IGFBP-5 (Bautista et al 1991, Nicolas et al 1995. On the basis of the findings that the complex of IGFBP-5 and IGFs, but not IGFs alone, binds to hydroxyapatite, we have proposed that the amount of IGFs stored in bone may be largely determined by the amount of IGFBP-5 produced by osteoblasts.…”

Section: Igfbp Binding To Putative Receptorsmentioning

confidence: 99%

“…On the basis of the findings that the complex of IGFBP-5 and IGFs, but not IGFs alone, binds to hydroxyapatite, we have proposed that the amount of IGFs stored in bone may be largely determined by the amount of IGFBP-5 produced by osteoblasts. In terms of the functional significance of IGFs stored in bone, we and others have proposed that IGFs fixed in bone via IGFBP-5 are eventually released during bone resorption in a bioactive form, to participate in the site-specific replacement of bone lost during bone resorption (Bautista et al 1991, Nicolas et al 1995. This process of site-specific replacement of bone lost during resorption is important, because otherwise the bone architecture would not provide efficient mechanical support.…”

Section: Igfbp Binding To Putative Receptorsmentioning

confidence: 99%

IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

Mohan

Baylink²

2002

Journal of Endocrinology

387

300

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Traditionally, binding proteins are known to regulate the activity of ligands by prolonging their half-life, and insulin-like growth factor (IGF)-binding proteins (IGFBPs) are no exception to this. The IGFBP family contains six high-affinity members with variable functions and mechanisms of actions. In addition to functioning as simple carrier proteins, IGFBPs in serum function to regulate the endocrine actions of IGFs by regulating the amount of IGF available to bind to signaling IGF-I receptors, whereas locally produced IGFBPs act as autocrine/paracrine regulators of IGF action. Furthermore, recent in vitro and in vivo findings that IGFBPs function independently of the IGFs as growth modulators are particularly exciting. Regarding the role of IGFBPs as ligand-independent growth modulators, our recent data that IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs provide evidence that IGFBP-5 itself is a growth factor that can act independently of IGFs to regulate bone formation. In terms of the mechanism by which certain IGFBPs mediate their effects in a ligand-independent manner, the binding of IGFBP to its putative receptor on the cell membrane may stimulate the signaling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBPs may also exert IGF-independent effects by transcriptional activation of genes by IGFBPs transported into the nucleus via their nuclear localization signal. In conclusion, IGFBPs are unusually pleotrophic molecules with functions ranging from the traditional role of prolonging the half-life of the IGFs to functioning as growth factors independent of the IGFs. In this regard, it was surprising to find that the human genome contains only about 35 000 genes. One mechanism to account for such complexity with a relatively small number of genes is strikingly illustrated by the multifunctional IGFBP class of proteins.

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“…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: 99%

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 ...

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Isolation of a novel insulin-like growth factor (IGF) binding protein from human bone: A potential candidate for fixing IGF-II in human bone

Cited by 169 publications

References 21 publications

Biological roles of insulin-like growth factor binding proteins (IGFBPs)

Biological roles of insulin-like growth factor binding proteins (IGFBPs)

IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

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

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