Subcutaneous administration of insulin-like growth factor (IGF)-II/IGF binding protein-2 complex stimulates bone formation and prevents loss of bone mineral density in a rat model of disuse osteoporosis

Conover, Cheryl A.; Johnstone, Edward W.; Turner, Russell T.; Evans, Glenda L.; Ballard, F. J.; Doran, Patrick M.; Khosla, Sundeep

doi:10.1016/s1096-6374(02)00044-8

Cited by 64 publications

(47 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Note added in proof In a recent study published by Conover et al 2002 the coadministration of IGFBP-2 and IGF stimulated bone formation II in rats and has been discussed as an potentially anabolic approach in the treatment of human osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates bone size and mass, but not density, in the absence and presence of growth hormone/IGF-I excess in transgenic mice

Eckstein

Pavicic

Nedbal

et al. 2002

Anatomy and Embryology

View full text Add to dashboard Cite

Insulin-like growth factor-binding protein-2 (IGFBP-2) has been suggested to be a negative regulator of bone growth and maintenance. The objective of this study was to characterize the effect of elevated IGFBP-2 on the skeletal phenotype of adult transgenic mice, in the absence and presence of growth hormone (GH) excess. 43 male mice were examined at an age of 4 months (7 IGFBP-2 transgenic mice, 12 GH transgenic mice, 10 mice carrying both transgenes, and 14 controls). The bone mineral content of the total skeleton and of isolated bones was quantified by dual energy X-ray absorptiometry (DXA), after validation versus ash analysis. Cortical and trabecular bone was quantified by peripheral quantitative computed tomography (pQCT), after validation versus microCT. A strong linear relationship was found between DXA and ash weight, and between pQCT and micro CT ( r>0.95). Bone size and bone mineral content were significantly reduced in IGFBP-2 transgenic mice, the magnitude of the effect varying between skeletal sites and between bone compartments. Elevated IGFBP-2 negatively modulated the GH-stimulated increase in bone size and mineral content, and completely blocked GH-effects at cortical sites. Notably, bone density was not decreased in IGFBP-2 transgenic animals compared with controls. In conclusion, IGFBP-2 is identified as a potent negative regulator of normal and GH-stimulated bone growth in vivo. Interestingly, elevated IGFBP-2 levels did not lead to a decrease in bone density, suggesting that IGFBP-2 negatively affects bone size and mineral content, but not bone maintenance in adult mice.

show abstract

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates bone size and mass, but not density, in the absence and presence of growth hormone/IGF-I excess in transgenic mice

Eckstein

Pavicic

Nedbal

et al. 2002

Anatomy and Embryology

View full text Add to dashboard Cite

show abstract

“…However, IGF1 administration only partially restores the deficit in the expression of osteoblast markers in aging animals (107), possibly because aging induces receptormediated skeletal resistance to IGF1 (108). In animal models of osteoporosis, systemic administration of IGF1 or IGF2/IGFBP2 promotes bone formation and prevents bone loss (109)(110)(111). Clinical trials revealed an increase in bone mineral density in some elderly normal and osteoporotic patients treated with low doses of GH or IGF1 (112)(113)(114).…”

Section: Growth Factorsmentioning

confidence: 99%

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Marie¹,

Kassem²

2011

European Journal of Endocrinology

187

143

View full text Add to dashboard Cite

Objective: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. Methods: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. Results and discussion: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

show abstract

“…In contrast, in vitro data indicated that IGFBP-2 in complex with IGF-II has high affinity for bone cell-derived extracellular matrix [Khosla et al, 1998] and is able to stimulate osteoblast proliferation under these conditions [Conover and Khosla, 2003]. In line with these results, subcutaneous administration of IGF-II/IGFBP-2 complexes stimulated bone formation and prevented loss of bone mineral density in a rat model of disuse osteoporosis pointing to a novel anabolic approach to increase bone mass in humans with osteoporosis [Conover et al, 2002].…”

Section: Igfbpsmentioning

confidence: 74%

Alteration of the insulin‐like growth factor axis during in vitro differentiation of the human osteosarcoma cell line HOS 58

Viereck

Siggelkow

Pannem

et al. 2007

J of Cellular Biochemistry

View full text Add to dashboard Cite

The insulin-like growth factors I and II (IGF-I, IGF-II), their receptors, and high affinity binding proteins (IGFBPs) represent a family of cellular modulators that play essential roles in the development and differentiation of cells and tissues including the skeleton. Recently, the human osteosarcoma cell line HOS 58 cells were used as an in vitro model of osteoblast differentiation characterized by (i) a rapid proliferation rate in low-density cells that decreased continuously with time of culture and (ii) an increasing secretion of matrix proteins during their in vitro differentiation. In the present paper, HOS 58 cells with low cell density at early time points of the in vitro differentiation (i) displayed a low expression of IGF-I and -II; (ii) synthesized low levels of IGFBP-2, -3, -4, and -5, but (iii) showed high expression levels of both the type I and II IGF receptors. During the in vitro differentiation of HOS 58 cells, IGF-I and -II expressions increased continuously in parallel with an upregulation of IGFBP-2, -3, -4, and -5 whereas the IGF-I receptor and IGF-II/M6P receptor mRNA were downregulated. In conclusion, the high proliferative activity in low cell density HOS 58 cells was associated with high mRNA levels of the IGF-IR, but low concentrations of IGFBP-2. The rate of proliferation of HOS 58 cells continuously decreased during cultivation in parallel with a decline in IGF-IR expression, but increase of mitoinhibitory IGFBP-2. These data are indicative for a role of the IGF axis during the in vitro differentiation of HOS 58 cells.

show abstract

Subcutaneous administration of insulin-like growth factor (IGF)-II/IGF binding protein-2 complex stimulates bone formation and prevents loss of bone mineral density in a rat model of disuse osteoporosis

Cited by 64 publications

References 38 publications

Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates bone size and mass, but not density, in the absence and presence of growth hormone/IGF-I excess in transgenic mice

Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates bone size and mass, but not density, in the absence and presence of growth hormone/IGF-I excess in transgenic mice

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Alteration of the insulin‐like growth factor axis during in vitro differentiation of the human osteosarcoma cell line HOS 58

Contact Info

Product

Resources

About