Circulating levels of IGF-I directly regulate bone growth and density
ABSTRACT IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis.
Full-textDOI: · Available from: Jan Frystyk, Sep 02, 2015
- SourceAvailable from: Kunal Sharan
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- "Congenital GH deficiency in humans and laboratory animals results in decreased bone growth and osteopenia (Kasukawa et al., 2004; Ohlsson et al., 1998). However, genetic and epidemiological evidence suggest that there is a correlation between serum IGF-1 and bone rather than serum GH and bone (Yakar et al., 2002). The mouse deficient for Igf1 or Igf1r in osteoblasts display osteopenia and reduced bone formation despite increased GH levels (Stabnov et al., 2002), whereas the mouse overexpressing Igf1 in osteoblast had increased bone mass (Zhao et al., 2000). "
ABSTRACT: Bones are structures in vertebrates that provide support to organs, protect soft organs, and give them shape and defined features, functions that are essential for their survival. To perform these functions, bones are constantly renewed throughout life. The process through which bones are renewed is known as bone remodeling, an energy demanding process sensitive to changes in energy homeostasis of the organism. A close interplay takes place between the diversity of nutritional cues and metabolic signals, with different elements of the hypothalamic circuits to co-ordinate energy metabolism with the regulation of bone mass. In this review, we focus on how mouse and human genetics have elucidated the roles of hormonal signals and neural circuits that originate in, or impinge on, the hypothalamus in the regulation of bone mass. This will help to understand the mechanisms whereby regulation of bone is gated and dynamically regulated by the hypothalamus.Best Practice & Research: Clinical Endocrinology & Metabolism 10/2014; DOI:10.1016/j.beem.2014.04.003 · 4.91 Impact Factor
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- "Growth hormone (GH) is responsible for longitudinal bone growth. A study elegantly demonstrated that a reduction in IGF-1 levels correlated with interstitial growth of long bones in mice (Yakar et al., 2002). It is also suggested that the localized activity of GH on the growth plate is mediated by elevated levels of IGF-1 production, with subsequent stimulation of chondrocyte proliferation and hypertrophy (Nilsson et al., 2005). "
ABSTRACT: Despite its natural healing potential, bone is unable to regenerate sufficient tissue within critical-sized defects, resulting in a non-union of bone ends. As a consequence, interventions are required to replace missing, damaged or diseased bone. Bone grafts have been widely employed for the repair of such critical-sized defects. However, the well-documented drawbacks associated with autografts, allografts and xenografts have motivated the development of alternative treatment options. Traditional tissue engineering strategies have typically attempted to direct in vitro bone-like matrix formation within scaffolds prior to implantation into bone defects, mimicking the embryological process of intramembranous ossification (IMO). Tissue-engineered constructs developed using this approach often fail once implanted, due to poor perfusion, leading to avascular necrosis and core degradation. As a result of such drawbacks, an alternative tissue engineering strategy, based on endochondral ossification (ECO), has begun to emerge, involving the use of in vitro tissue-engineered cartilage as a transient biomimetic template to facilitate bone formation within large defects. This is driven by the hypothesis that hypertrophic chondrocytes can secrete angiogenic and osteogenic factors, which play pivotal roles in both the vascularization of constructs in vivo and the deposition of a mineralized extracellular matrix, with resulting bone deposition. In this context, this review focuses on current strategies taken to recapitulate ECO, using a range of distinct cells, biomaterials and biochemical stimuli, in order to facilitate in vivo bone formation. Copyright © 2014 John Wiley & Sons, Ltd.Journal of Tissue Engineering and Regenerative Medicine 06/2014; 9(8). DOI:10.1002/term.1918 · 4.43 Impact Factor
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- "In addition, muscle mass appears to play a role in the interplay between adipose and bone tissue, likely by mechanical stimuli and also by myokines and other factors secretion . Indeed, muscle is also source of IGF-1, known to be one of the factors which cooperate in the maintenance of skeletal health .In addition, lower levels of IGF-1 [27, 41] have been found in obese individuals (unpublished observation) and IGF-1 might play a pivotal role in the mechanism linking obesity to decreased bone density and bone quality , by mechanism due to altered osteoblast homeostasis. Indeed, the recent in vivo results, showing a weak increase in osteoclastogenic factors, go against the hypothesis that production of adipokines and inflammatory cytokines by adipose tissue lead to an increased bone resorption inducing a decrease in bone volume [28, 44]. "
ABSTRACT: Obesity and sarcopenia have been associated with mineral metabolism derangement and low bone mineral density (BMD). We investigated whether imbalance of serum factors in obese or obese sarcopenic patients could affect bone cell activity in vitro. To evaluate and characterize potential cellular and molecular changes of human osteoblasts, cells were exposed to sera of four groups of patients: (1) affected by obesity with normal BMD (O), (2) affected by obesity with low BMD (OO), (3) affected by obesity and sarcopenia (OS), and (4) affected by obesity, sarcopenia, and low BMD (OOS) as compared to subjects with normal body weight and normal BMD (CTL). Patients were previously investigated and characterized for body composition, biochemical and bone turnover markers. Then, sera of different groups of patients were used to incubate human osteoblasts and evaluate potential alterations in cell homeostasis. Exposure to OO, OS, and OOS sera significantly reduced alkaline phosphatase, osteopontin, and BMP4 expression compared to cells exposed to O and CTL, indicating a detrimental effect on osteoblast differentiation. Interestingly, sera of all groups of patients induced intracellular alteration in Wnt/ β -catenin molecular pathway, as demonstrated by the significant alteration of specific target genes expression and by altered β -catenin cellular compartmentalization and GSK3 β phosphorylation. In conclusion our results show for the first time that sera of obese subjects with low bone mineral density and sarcopenia significantly alter osteoblasts homeostasis in vitro, indicating potential detrimental effects of trunk fat on bone formation and skeletal homeostasis.International Journal of Endocrinology 05/2014; 2014:278316. DOI:10.1155/2014/278316 · 1.52 Impact Factor