Insulin-Like Growth Factor-I Augments Chondrocyte Hypertrophy and Reverses Glucocorticoid-Mediated Growth Retardation in Fetal Mice Metatarsal Cultures

Mushtaq, Talat; Bijman, P; Ahmed, S. Faisal; Farquharson, Colin

doi:10.1210/en.2003-1435

Cited by 64 publications

(90 citation statements)

References 45 publications

(46 reference statements)

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“…Our previous studies have shown that IGF-I plays a major role in promoting longitudinal growth in the mouse metatarsal model (Mushtaq et al 2004). Furthermore, the growth inhibitory effect of dexamethasone was reversed in this model following exposure to IGF-I (Mushtaq et al 2004).…”

Section: Discussionmentioning

confidence: 77%

“…Furthermore, the growth inhibitory effect of dexamethasone was reversed in this model following exposure to IGF-I (Mushtaq et al 2004). However, the growth inhibitory effects of TNF-a and IL-1b are only partially reversed following treatment with IGF-I (Martensson et al 2004), suggesting that some of the effects of these proinflammatory cytokines may be IGF-I independent.…”

Section: Discussionmentioning

confidence: 77%

“…05 mg/ml gentamycin and 1 . 25 mg/ml fungizone (Invitrogen; Mushtaq et al 2004). C2-ceramide was added at a final concentration of 40, 30, 20 and 10 mM for an 8-day period.…”

Section: Organ Culturementioning

confidence: 99%

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Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

MacRae¹,

Burdon²,

Ahmed³

et al. 2006

Journal of Endocrinology

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Proinflammatory cytokines inhibit growth plate development. However, their underlying mechanisms of action are unclear. These effects may be mediated by ceramide, a sphingosine-based lipid second messenger, which is elevated in a number of chronic inflammatory diseases. To test this hypothesis, we determined the effects of C2-ceramide, a cell permeable ceramide analogue, on the growth of the ATDC5 chondrogenic cell line and on cultured fetal mice metatarsals. In ATDC5 cells, C2-ceramide significantly induced apoptosis at both 40 (82%; P!0 . 05) and 25 mM (53%; P!0 . 05). At 40 mM, C2-ceramide significantly reduced proliferation ([ 3 H]-thymidine uptake/mg protein) (62%; P!0 . 05). C2-ceramide did not markedly alter the differentiation state of the cells as judged by the expression of markers of chondrogenesis and differentiation (sox 9, collagen II and collagen X). The IGF-I signalling pathway is the major autocrine/paracrine regulator of bone growth. Both in the presence and absence of IGF-I, C2-ceramide (25 mM) induced an equivalent reduction in proliferation (60%; P!0 . 001). Similarly, C2-ceramide (40 mM) induced a 31% reduction in fetal metatarsal growth both in the presence and absence of IGF-I (both P!0 . 001). Furthermore, C2-ceramide reduced ADCT5 proliferation in the presence of AG1024, an IGF-I and insulin receptor blocker. Therefore, C2-ceramide-dependent inhibition appears to be independent of IGF-mediated stimulation of bone growth. Indeed, biochemical studies demonstrated that C2-ceramide (25 mM) pretreatment did not alter IGF-I-stimulated phosphorylation of insulin receptor substrate-1, Akt or P44/42 MAP kinase. In conclusion, C2-ceramide inhibits proliferation and induces apoptosis in growth plate chondrocytes through an IGF-I independent mechanism.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 77%

See 1 more Smart Citation

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

MacRae¹,

Burdon²,

Ahmed³

et al. 2006

Journal of Endocrinology

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“…(43) The middle three metatarsals were isolated from 17-day-old embryos under a dissecting microscope. Metatarsals were cultured in 24-well plates (Costar, High Wycombe, UK) with one bone per well in 300 mL aMEM medium (without ribonucleosides) supplemented with 0.2% BSA (Fraction V), 5 mg/mL L-ascorbic acid phosphate, 1 mM b-glycerophosphate, 0.05 mg/mL gentamicin, and 1.25 mg/mL fungizone.…”

Section: Embryonic Metatarsal Organ Culturementioning

confidence: 99%

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Pass

MacRae

Huesa

et al. 2012

Journal of Bone and Mineral Research

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Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2 À/À mice, which has normal systemic insulin-like growth factor 1 (IGF-1) levels. The local effects of GH on bone growth are equivocal, and therefore this study aimed to understand better the SOCS2 signaling mechanisms mediating the local actions of GH on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain-and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, -3, and -5 phosphorylation was increased in SOCS2 À/À chondrocytes but not in cells overexpressing SOCS2. This increased chondrocyte STAT signaling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2À/À embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data, bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2 À/À 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2 À/À mouse represents a valid model for studying the local effects of GH on bone growth. ß

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“…More recently, a number of investigators have used ex vivo models such as rodent metatarsals in culture (Mårtensson et al 2004, Mushtaq et al 2004. For example, when fetal mouse metatarsals were cultured for up to 10 days with either daily or alternate-day dexamethasone at 10 −6 M, dexamethasone-treated bones paralleled control bone growth rate until day 8 when their rate of growth decreased resulting in a total length that was significantly reduced from controls at days 8 and 10 (Mushtaq et al 2004).…”

Section: Techniques To Assess Bone Growth Ratementioning

confidence: 99%

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

Wood

Souček

Wong

et al. 2018

Journal of Endocrinology

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Glucocorticoids (GCs) are effective for the treatment of many chronic conditions, but their use is associated with frequent and wide-ranging adverse effects including osteoporosis and growth retardation. The mechanisms that underlie the undesirable effects of GCs on skeletal development are unclear, and there is no proven effective treatment to combat them. An in vivo model that investigates the development and progression of GC-induced changes in bone is, therefore, important and a wellcharacterized pre-clinical model is vital for the evaluation of new interventions. Currently, there is no established animal model to investigate GC effects on skeletal development and there are pros and cons to consider with the different protocols used to induce osteoporosis and growth retardation. This review will summarize the literature and highlight the models and techniques employed in experimental studies to date.

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Insulin-Like Growth Factor-I Augments Chondrocyte Hypertrophy and Reverses Glucocorticoid-Mediated Growth Retardation in Fetal Mice Metatarsal Cultures

Cited by 64 publications

References 45 publications

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

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