IGF-I increases markers of osteoblastic activity and reduces bone resorption via osteoprotegerin and RANK-ligand

Abstract

BackgroundBone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone.MethodsSeveral proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice, Igf+/+, n = 10), heterozygous Igf+/- group with partial IGF-I deficiency (Hz, n = 10), and heterozygous Igf+/- mice treated with IGF-I for 10 days (Hz + IGF-I, n = 10).ResultsData in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity.ConclusionsLow doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor.

IGF-1 modulates gene expression of proteins involved in inflammation, cytoskeleton, and liver architecture

“…The preference for IGF-1 treatment at low doses was chosen following the experience acquired from previous studies belonging to the same model [4–6, 8, 9, 11, 13, 14, 18, 21, 24, 35, 39, 40, 45]. Briefly, such dosage is enough to restore normal circulating IGF-1 values without inducing hypoglycemia and any adverse effects.…”

“…Moreover, its deficiency has been initially related to different pathologies, such as Laron’s syndrome, intrauterine growth restriction (IUGR), liver cirrhosis, metabolic syndrome, and aging-related disorders, among others [22, 24, 28, 32, 38, 42, 43, 47, 49]. …”

Modulatory effects of l-arginine and soy enriched diet on bone homeostasis abnormalities in streptozotocin-induced diabetic rats

“…IGF-1 could stimulate the formation of osteocalcin, collagen and non-collagenous matrix proteins by differentiated osteoblasts and increase the number of functional osteoblasts by promoting osteoprogenitor cell replication [45]. It has been found that IGF-1 deficiency was associated with hypoexpression of OPG and Runx2 genes and overexpression of RANKL resulting in promotion of the osteoclastic activity and osteoblastic inhibition [46]. Furthermore, high glucose concentrations significantly impair the proliferative and functional responses of osteoblastic cells to IGF-I [47] and inhibit the osteogenic differentiation [48].…”

Partial IGF‐1 deficiency induces brain oxidative damage and edema, which are ameliorated by replacement therapy

“…According to previous series [26,27], 5 6 1 month old heterozygous mice (Hz) showed a significant decrease of circulating levels of IGF-1 as compared with control animals (WT), which was normalized by the exogenous administration of low doses of IGF-1 (2 mg/100 g body weight/day, for 10 days). Thus, the usefulness of the substitutive IGF-1 therapy was confirmed ( Fig.…”

“…With this perspective, the present study was aimed to evaluate, in a novel experimental model of mice with partial IGF-1 deficiency [26,27], the following: 1) brain morphological damage, assessed by histopathological studies (number and shape of cells by Nissl staining) and nuclear magnetic resonance imaging (MRI, hydric content and ventricular area); 2) oxidative damage by lipid oxidative (MDA) and hypoxic/ischemic damage (lactate) markers; 3) cerebral gene expression of proteins involved in cellular protection (such as HSPs), inflammation and cell death; and 4) brain function determined by learning and memory tests.…”