The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

Fritton, J. Christopher; Kawashima, Yuki; Mejía, Wilson; Williams, Courtland, Hayden; Elis, Sébastien; Sun, Hui; Wu, Yinjgie; Rosen, Clifford J.; Clemmons, David R.; Yakar, Shoshana

doi:10.1074/jbc.m109.041913

Cited by 21 publications

(15 citation statements)

References 37 publications

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“…We found that ALSKO mice had significantly lower osteoclast number formed in vitro than WT cultures. These results are in agreement with our previous studies showing impaired osteoclastogenesis in bone marrow extracted from young ALSKO mice (Fritton et al 2010;Yakar et al 2009b). …”

Section: Discussionsupporting

confidence: 94%

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Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging

Courtland

Kennedy²,

et al. 2012

AGE

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Studies linking insulin-like growth factor-1 (IGF-1) to age-related bone loss in humans have been reported but remain only correlative. In this investigation, we characterized the bone phenotype of aged WT C57BL/6J male mice in comparison to that of C57BL/ 6J mice with reduced serum IGF-1 levels arising from an igfals gene deletion (ALS knockout (ALSKO)). During the aging process, WT mice showed an increase in fat mass and decrease lean mass while ALSKO mice had stable lean and fat mass values. Skeletal analyses of femora from WT mice revealed an expansion of the marrow area and a significant accumulation of intracortical porosity associated with increased intracortical remodeling. In contrast, ALSKO mice showed only small age-related declines in the amount of cortical bone tissue and minimal intracortical porosity, at 2 years of age. Accordingly, mechanical tests of femora from 2-year-old WT mice revealed reduced stiffness and maximal load when compared to bones from ALSKO mice. We show here that lifelong reductions in serum IGF-1 compromise skeletal size in development leading to slender bones; they are also associated with decreased intracortical bone remodeling and preservation of bone strength during aging.

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Section: Discussionsupporting

confidence: 94%

“…4). These findings are in agreement with our previous study, showing decreased osteoclastogenesis in ALSKO mice during growth (Fritton et al 2010).…”

Section: Effects Of Decreases In Serum Igf-1 On Bone Remodeling Durinsupporting

confidence: 94%

Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging

Courtland

Kennedy²,

et al. 2012

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“…The effects of IGFBP-3 on adipocyte differentiation have been variable. IGFBP-3 deficiency or hIGFBP-3 supplementation did not affect bone marrow adipocytes in culture (43), whereas hIGFBP-3 inhibited the differentiation of 3T3-L1 cells and rat preadipocytes in vitro (39,42). In contrast, hIGFBP-3 enhanced adipocyte differentiation and stimulated the lipogenic enzyme glycerol-3-phosphate dehydrogenase in visceral and sc preadipocytes (44).…”

Section: Discussionmentioning

confidence: 87%

“…Remarkably, aging PGKmutBP3 mice had reduced expression of the BAT signature UCP1, which was not expected in the presence of increased free IGF-1, because IGF-1 plays an important role in the thermogenic differentiation of brown adipocytes (16,17). Impaired integration of IGF-1 into ternary complex formation may provide an alternative explanation, given the similarity between bone marrow adipocytes and BAT (43). To determine whether IGF-1 expression is altered in BAT, we measured IGF-1 mRNA ex vivo.…”

Section: Discussionmentioning

confidence: 96%

“…It has also been suggested that ternary complex formation between IGF-1, IGFBP-3, and ALS is important for adipogenesis. Lack of ternary complex formation due to ALS deletion was associated with increased adipogenesis from bone marrowderived mesenchymal stromal cells in culture, whereas recombinant ALS inhibited adipogenesis (43). Although ALS-deficient mice had normal body composition and insulin sensitivity (45), humans with ALS deficits are insulinresistant (46,47) and may be obese (47).…”

Section: Discussionmentioning

confidence: 99%

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Glucose Intolerance in Aging Male IGFBP-3 Transgenic Mice: Differential Effects of Human IGFBP-3 and Its Mutant IGFBP-3 Devoid of IGF Binding Ability

et al. 2014

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We have reported a reduction of insulin secretion and glucose intolerance in young mice overexpressing human IGFBP-3 (phosphoglycerate kinase [PGK]BP3) or its mutant Gly56/Gly80/Gly81-IGFBP-3 (PGKmutBP3) under the PGK promoter. Here, we investigated changes in glucose and lipid homeostasis with age in PGKBP3 and PGKmutBP3 mice compared with wild-type mice. Body weight, glucose tolerance, insulin tolerance, visceral fat, interscapular brown adipose tissue (BAT), serum lipids, and pancreas histology were examined at age 3, 6, and 12 months. Murine IGFBP-3 was similar in all mouse genotypes and decreased with age in parallel with total IGF-1. Visceral fat and BAT masses increased in PGKmutBP3 mice, but not in PGKBP3 mice. Glucose tolerance was impaired in both PGKBP3 and PGKmutBP3 mice. However, PGKBP3 mice had increased expression of uncoupling protein-1 in BAT and reduced adiposity, and continued to have smaller pancreatic β-cell mass and reduced insulin secretion through age 12 months. In contrast, PGKmutBP3 mice developed insulin resistance with age in association with pancreatic β-cell hyperplasia, impaired expression of uncoupling protein-1 in BAT, and increased adiposity. In addition, both PGKBP3 and PGKmutBP3 mice had elevated glycerol in the circulation, but only PGKBP3 mice had elevated free fatty acids and only PGKmutBP3 mice had elevated triglycerides. Estimated free IGF-1 did not increase with age in transgenic mice, as it did in wild-type mice. Thus, overexpression of human IGFBP-3 or its mutant devoid of IGF binding ability leads to glucose intolerance with, however, different effects on insulin secretion, insulin sensitivity, and lipid homeostasis in aging mice.

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Sex-specific regulation of body size and bone slenderness by the acid labile subunit

Courtland¹,

DeMambro²,

Maynard³

et al. 2010

Journal of Bone and Mineral Research

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Insulin-like growth factor-1 (IGF-1) is a crucial mediator of body size and bone mass during growth and development. In serum, IGF-1 is stabilized by several IGF-1 binding proteins (IGFBPs) and the acid labile subunit (ALS). Previous research using ALS knockout (ALSKO) mice indicated a growth retardation phenotype and clinical reports of humans have indicated short stature and low bone mineral density (BMD) in patients with ALS deficiency. To determine the temporal and sex-specific effects of ALS deficiency on body size and skeletal development during growth we characterized control and ALSKO mice from 4 to 16 weeks of age. We found that female ALSKO mice had an earlier onset reduction in body size (4 weeks), but that both female and male ALSKO mice were consistently smaller than control mice. Interestingly, skeletal analyses at multiple ages showed increased slenderness of ALSKO femora that was more severe in females than in males. Both male and female ALSKO mice appeared to compensate for their more slender bones through increased bone formation on their endosteal surfaces during growth, but ALSKO females had increased endosteal bone formation compared to ALSKO males. This study revealed age and sex-specific dependencies of ALS deficiency on body size and bone size. These findings may explain the heterogeneity in growth and BMD measurements reported in human ALS deficient patients.

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The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

Cited by 21 publications

References 37 publications

Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging

Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging

Glucose Intolerance in Aging Male IGFBP-3 Transgenic Mice: Differential Effects of Human IGFBP-3 and Its Mutant IGFBP-3 Devoid of IGF Binding Ability

Sex-specific regulation of body size and bone slenderness by the acid labile subunit

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