Differential expression of IGF system components in proliferating vs. differentiating growth plate chondrocytes: the functional role of IGFBP-5

Kiepe, Daniela; Ciarmatori, Sonia; Haarmann, Anke; Tönshoff, Burkhard

doi:10.1152/ajpendo.00363.2005

Cited by 43 publications

(38 citation statements)

References 41 publications

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“…Quite strikingly, OA chondrocytes were particularly well responsive to the treatment by rAAV IGF-I here, in marked contrast with their otherwise established hyporesponsiveness to the growth factor (59,72). Of note, we also observed that IGF-I overexpression in OA cartilage in situ was capable of significantly decreasing the expression of IGFBP3 and IGFBP4, two inhibitors of the IGF-I actions (40)(41)(42), while increasing the levels of two of its potentiators (IGFBP5 and its own receptor [IGF-IR]) (42,43), an effect noted at prolonged time points and probably the result of the steady levels of IGF-I production from the rAAV transgene sequence. In this regard, the effects of IGF-I on these components of the IGF-I axis via rAAV in OA cartilage are in good agreement with previous findings when providing IGF-I as a recombinant molecule to articular chondrocytes in vitro (73)(74)(75)(76).…”

Section: Discussionmentioning

confidence: 77%

“…We also analyzed the extent by which the candidate treatment with the rAAV-human IGF-I (rAAV-hIGF-I) vector was capable of durably restoring the structure of human OA cartilage vis-à-vis normal cartilage. Finally, we investigated the influence of rAAV-mediated IGF-I production upon the expression of key effectors of the IGF-I axis, specifically the IGF-binding proteins 3, 4 and 5 (IGFBP-3 to IGFBP-5) as well as the IGF-I receptor (IGF-IR) and downstream mitogenactivated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK-1/2) and phosphatidylinisitol-3/Akt (PI3K/Akt) signal transduction pathways (33)(34)(35)(36)(37)(38)(39), reported as being inhibitors (IGFBP3 and IGFBP4) (40)(41)(42) or potentiators (IGFBP5 and IGF-IR) (42,43) of the IGF-I actions during OA pathogenesis.…”

Section: Benefits Of Recombinant Adeno-associated Virus (Raav)-mediatmentioning

confidence: 99%

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Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

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Administration of therapeutic genes to human osteoarthritic (OA) cartilage is a potential approach to generate effective, durable treatments against this slow, progressive disorder. Here, we tested the ability of recombinant adeno-associated virus (rAAV)-mediated overexpression of human insulinlike growth factor (hIGF)-I to reproduce an original surface in human OA cartilage in light of the pleiotropic activities of the factor. We examined the proliferative, survival and anabolic effects of the rAAV-hIGF-I treatment in primary human normal and OA chondrocytes in vitro and in explant cultures in situ compared with control (reporter) vector delivery. Efficient, prolonged IGF-I secretion via rAAV stimulated the biological activities of OA chondrocytes in all the systems evaluated over extended periods of time, especially in situ, where it allowed for the long-term reconstruction of OA cartilage (at least for 90 d). Remarkably, production of high, stable amounts of IGF-I in OA cartilage using rAAV advantageously modulated the ex-

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Section: Discussionmentioning

confidence: 77%

Section: Benefits Of Recombinant Adeno-associated Virus (Raav)-mediatmentioning

confidence: 99%

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

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“…In this regard, it is known that IGFBP-5 potentiated IGF-I actions on chondrocyte differentiation (21). Furthermore, it has also been shown that IGF-I stimulates IGFBP-5 expression in chondrocytes (22).…”

Section: Discussionmentioning

confidence: 98%

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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“…The software provided from the company allowed the quantitative detection of fluorescence by the incorporation of the substance SyberGreen into the amplification products. Amplification was performed in the presence of Universal Mastermix (PE Applied Biosystems) with SyberGreen to detect PCR products at the end of each amplification step, and the results were analyzed as already reported (Kiepe et al 2006).…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

“…For total cell homogenate cells were incubated with the indicated substances, scraped in 50 ml ice-cold lysis buffer containing a mixture of proteinase and phosphatase inhibitors, and cell extracts were treated as reported previously (Hömme et al 2003, Kiepe et al 2006. Cytosol membrane and nuclear factions of cells were prepared by previously described procedures (Hoeflich et al 2004).…”

Section: Western Immunoblottingmentioning

confidence: 99%

Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3.1C5.18 in response to IGF-I

Ciarmatori¹,

Kiepe²,

Haarmann³

et al. 2007

Journal of Molecular Endocrinology

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Since IGF-I is an important chondrocyte growth factor, we sought to examine the intracellular mechanisms by which it exerts two of its pivotal effects, stimulation of proliferation and differentiation. We used the mesenchymal chondrogenic cell line RCJ3.1C5.18, which progresses spontaneously to differentiated growth plate chondrocytes. This differentiation process could be enhanced by exogenous IGF-I. Pharmacological inhibition of the phosphatidylinositol-3 (PI-3) kinase by LY294002, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 by U0126, the protein kinase (PK) A pathway by H-89 or KT5720, and the PKC pathway by bisindolylmaleimide suppressed IGF-I-stimulated cell proliferation. In contrast, IGF-I-enhanced early cell differentiation, as assessed by collagen type II and aggrecan gene expression, was not affected by MAPK/ERK1/2 pathway inhibition, but significantly diminished by inhibition of the PI-3 kinase, the PKC and the PKA pathway. Moreover, terminal differentiation of chondrocytes in response to IGF-I, as assessed by gene expression of alkaline phosphatase, Indian hedgehog, and collagen type X, were only interrupted by PI-3 kinase pathway inhibition. In conclusion, IGF-I exerts its differential effect on chondrocyte proliferation vs differentiation through the use of at least four partially interacting intracellular signaling pathways, whose activity is temporarily regulated. When chondrocytes progress from proliferating cells to early and terminal differentiating cells, they progressively inactivate IGF-I-related intracellular signaling pathways. This mechanism might be essential for the complex and cell stage-specific anabolic action of IGF-I in the growth plate.

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Differential expression of IGF system components in proliferating vs. differentiating growth plate chondrocytes: the functional role of IGFBP-5

Abstract: Kiepe, Daniela, Sonia Ciarmatori, Anke Haarmann, and Burkhard Tönshoff. Differential expression of IGF system components in proliferating vs. differentiating growth plate chondrocytes: the functional role of IGFBP-5.

Cited by 43 publications

References 41 publications

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

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

Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3.1C5.18 in response to IGF-I

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