Interleukin-1β and TNF-α Act in Synergy to Inhibit Longitudinal Growth in Fetal Rat Metatarsal Bones

Mårtensson, Katarina; Chrysis, Dionisios; Sävendahl, Lars

doi:10.1359/jbmr.040805

Cited by 153 publications

(186 citation statements)

References 24 publications

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“…This effect has been reported to be independent of the concurrent reduction in growth associated with glucocorticoid therapy (Tynjala et al 2006). TNF-a and IL-1b may directly inhibit growth plate chondrocyte dynamics as well as longitudinal growth in vitro (Martensson et al 2004, MacRae et al 2006b), however, the underlying mechanisms that lead to these effects are unclear.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Then, we examined the expression of genes encoding cytokines that were reported to affect endochondral ossification. 17,[29][30][31] As shown in Figure 6c, among the cytokines examined, Il-1β and Mcp-5 displayed big differences between Ikkβ Prx1KO and control mice. Although IL-1β is reported to inhibit the differentiation of chondrocytes, 29,32 it was downregulated in the perichondrium of Ikkβ Prx1KO mice and thus fails to explain the phenotype.…”

Section: Resultsmentioning

confidence: 82%

IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

et al. 2014

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IκB kinase β (IKKβ) is a catalytic subunit of the IKK complex, which activates nuclear factor-κB (NF-κB). Although its role in osteoclastogenesis is well established, the role of IKKβ in bone formation is poorly understood. Here, we report that conditional knockout of Ikkβ in limb bud mesenchymal cells results in the upregulation of monocyte chemoattractant protein-5 (MCP-5) in the perichondrium, which in turn inhibits the growth of longitudinal bone by compromising chondrocyte hypertrophy and increasing the apoptosis of chondrocytes within the growth plate. Contrary to expectations, IKKβ in cells of chondrocyte or osteoblast lineage was dispensable for bone growth. On the other hand, ex vivo experiments confirmed the role of MCP-5 in the growth of longitudinal bone. Furthermore, an in vitro study demonstrated that the action of IKKβ on MCP-5 is cell autonomous. Collectively, our results provide evidence for a previously unrecognized role of IKKβ in the regulation of the growth plate that is mediated through stimulation-independent downregulation of MCP-5 in the perichondrium.

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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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Interleukin-1β and TNF-α Act in Synergy to Inhibit Longitudinal Growth in Fetal Rat Metatarsal Bones

Cited by 153 publications

References 24 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

IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

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

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