Human fetal and adult chondrocytes. Effect of insulinlike growth factors I and II, insulin, and growth hormone on clonal growth.

Vetter, U.; Zapf, J.; Heit, W; Helbing, G.; Heinze, E.; Froesch, E. R.; Teller, W. M.

doi:10.1172/jci112518

Cited by 120 publications

(24 citation statements)

References 32 publications

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“…Few facts are currently available about the effects mediated by the IGF-I1 receptors. Several studies have shown that IGF-II at low concentrations stimulates [3H]thymidine incorporation into DNA and also induces multiplication of a number of different cells (6,(22)(23)(24)(25)(26). However, it has been proposed that the effect of low concentrations of IGF-II on fetal rat brain DNA synthesis is mediated through the IGF-I receptor (26).…”

Section: Resultsmentioning

confidence: 99%

Regulation of insulin-like growth factor II receptors by growth hormone and insulin in rat adipocytes.

Lönnroth¹,

AssMUNDSSON²,

Edén³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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The acute and long-term effects of growth hormone (GH) on the binding of insulin-like growth factor II (IGF-II) were evaluated in adipose cells from hypophysectomized rats given replacement therapy with thyroxine and hydrocortisone and in cells from their sham-operated littermates. After the cells were incubated with insulin and/or GH, the recycling ofIGF-ll receptors was metabolically inhibited by treating the cells with KCN. IGF-ll binding was 100 ± 20% higher in cells from GH-deficient animals when compared with sham-operated controls. These GH-deficient cells also showed an increased sensitivity for insulin as compared with control cells (the ECso for insulin was 0.06 ng/ml in GH-deficient cells and 0.3 ng/ml in control cells). However, the maximal incremental effect of insulin on IGF-H binding was reduced -27% by hypophysectomy. GH added to the incubation medium increased the number of IGF-ll binding sites by 100 ± 18% in cells from hypophysectomized animals. This increase was rapidly induced (til2, -10 min), but the time course was slower than that for the stimulatory effect of insulin. Half-maximal effect of GH on IGF-ll binding was obtained at =30 ng/ml.Thus, GH added in vitro exerted a rapid insulin-like effect on the number of IGF-ll receptors. GH also appears to play a regulating role for maintaining the cellular number of IGF-II receptors and, in addition, modulates the stimulatory effect of insulin on IGF-II binding.The insulin-like growth factors (IGF)-I and -II bind to specific receptors that mediate their growth-promoting effects (1, 2). The mechanisms for the growth-promoting effect of GH are still unclear. Recent data suggest that GH mediates cell differentiation, whereas the IGFs promote clonal expansion (3). Moreover, GH stimulates cellular production of IGF-I (4, 5).Both IGF-I and -II bind to insulin receptors and crossreact with each other's receptors with reduced affinity (1, 2, 6). A further interaction between these hormones is that the cellular binding of IGF-II to fat cells is increased following insulin exposure (2). Recently, the insulin-mediated increase of IGF-II binding to rat adipocytes was shown to be due to a recruitment of receptors from an intracellular pool to the plasma membrane (7). This effect markedly resembles the effect of insulin on the recruitment of glucose transport units (8, 9).Rat (10) and human (11) adipose cells possess specific cellular surface receptors for growth hormone (GH). GH produces insulin-like effects in these cells-such as enhancement of glucose metabolism and transport as well as inhibition of lipolysis (12)(13)(14).To elucidate whether GH exerts a regulatory effect on the cellular number of IGF-II receptors the effect of GH on IGF-II binding was studied in adipose cells from hypophysectomized rats and their sham-operated littermates. METHODSTissue Source. Male Sprague-Dawley rats, weighing 150-160 g, were hypophysectomized according to procedures described elsewhere (15). Each set of experiments was compared with data from sham-operated li...

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Section: Resultsmentioning

confidence: 99%

Regulation of insulin-like growth factor II receptors by growth hormone and insulin in rat adipocytes.

Lönnroth¹,

AssMUNDSSON²,

Edén³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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“…The latter continues until the soft callus is completely replaced by bone and this new bone bridges the fracture gap. These stages involve proliferation of chondrocytes and cells of the osteoblast lineage, and IGFs are important regulators of both cell types (Vetter et al 1986, McCarthy et al 1989, Wergedal et al 1990, Conover & Rosen 2002. In vitro data have shown that PAPP-A protein and IGFBP-4 proteolytic activity are present in media conditioned by human osteoblasts and rabbit periosteal chondrocytes (AuwYang et al 2003, Ortiz et al 2003.…”

Section: Discussionmentioning

confidence: 99%

“…IGF-I and IGF-I receptor expression have been shown to have widespread distribution within the callus in most cell types and differentiation stages of the osteoblast lineage, in the newly proliferating and early hypertrophic chondrocytes, and in mesenchymal cells (Andrew et al 1993, Trippel 1998, Okazaki et al 2003, Wildemann et al 2004. Moreover, IGFs are mitogenic in vitro for cells important in fracture healing, including chondrocytes and osteoblasts, and IGF-I has been shown to stimulate proteoglycan synthesis in growth plate chondrocytes and collagen synthesis in bone (Vetter et al 1986, McCarthy et al 1989, Wergedal et al 1990, Conover & Rosen 2002.…”

Section: Introductionmentioning

confidence: 99%

Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice

Miller¹,

Bronk²,

Nishiyama³

et al. 2007

Journal of Endocrinology

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Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that regulates IGF bioavailability in vitro through cleavage of inhibitory IGF-binding protein-4 (IGFBP-4), has been implicated in skeletal development and injury repair responses. However, direct in vivo data are lacking. In this study, we used PAPP-A knock-out (KO) mice to determine the role of PAPP-A in fracture repair. Stabilized mid-shaft fractures were produced in femurs of 3-month-old mice. At 14 days post-fracture, complete bony bridging of the fracture callus was seen radiographically in wild-type but not in PAPP-A KO mice. Histological examination 5 to 28 days post-fracture showed reductions in the amount of intramembranous bone formation, cartilage production, endochondral ossification and remodeling in PAPP-A KO compared with wild-type mice. However, fracture healing appeared similar in both groups at 42 days post-fracture when analyzed by histology. A similar degree of healing strength in wild-type and PAPP-A KO femurs was demonstrated by mechanical testing at 28 and 42 days post-fracture. Untreated cultures of day 5 fracture calluses from wild-type mice showed robust IGFBP-4 protease activity and IGF receptor phosphorylation, whereas fracture calluses from PAPP-A KO mice had no IGFBP-4 protease activity and reduced IGF receptor phosphorylation. These data demonstrate a marked delay in fracture healing in PAPP-A KO compared with wild-type mice, and suggest that PAPP-A is necessary in the early phases of the process for expeditious fracture repair. The ability of PAPP-A to enhance local IGF action may be an important mechanism for optimizing the fracture repair response.

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“…This balance is disturbed in rheumatoid arthritis and other inflammatory or degenerative joint diseases [3,4]. Recent studies from several laboratories have demonstrated that the steady state metabolism of chondrocytes is affected by factors such as insulin-like growth factors IGF-I and IGF-II [5,6], transforming growth factor [7,8], and interleukin-1 (IL-1) [9][10][11][12][13][14][15]. Increased concentrations of interleukin-6 have been found in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis, and crystal-related joint diseases [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐1β induces synthesis and secretion of interleukin‐6 in human chondrocytes

et al. 1990

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Increased concentrations of interleukin‐6 (IL‐6) have been found in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and crystal‐related joint deseases. It is therefore of great interest to identify the cells responsible for the production of IL‐6, and to investigate whether IL‐6 plays a role in the pathogenesisof degenerative or inflammatory joint diseases. Here we show that human interleukin‐1β (IL‐1β) induces IL‐6 synthesis and secretion in differentiated human chondrocytes. In organ cultures resembling closely the in vivo system 106 chondrocytes incubated with 100 units of interleukin‐1β per ml of medium led to the release of 6 × 103 units of IL‐6 within 24 h. Chondrocytes cultured in agarose or as monolayers similary incubated with IL‐1β produced even higher amounts of IL‐6: 70 × 103 units per 106 cells within 24 h. The induction of IL‐6 synthesis by IL‐1β was also shown at the mRNA level. IL‐6 secreted by stimulated chondrocytes showed heterogeneity upon Western blot analysis.

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Human fetal and adult chondrocytes. Effect of insulinlike growth factors I and II, insulin, and growth hormone on clonal growth.

Abstract: The results are compatible with the concept that IGF II is a more potent stimulant of clonal growth of chondrocytes during fetal life, whereas IGF I is more effective in stimulating clonal growth of chondrocytes during postnatal life.

Cited by 120 publications

References 32 publications

Regulation of insulin-like growth factor II receptors by growth hormone and insulin in rat adipocytes.

Regulation of insulin-like growth factor II receptors by growth hormone and insulin in rat adipocytes.

Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice

Interleukin‐1β induces synthesis and secretion of interleukin‐6 in human chondrocytes

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