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.
Highlights
Bone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I)
The pathogenesis of osteopenia in liver cirrhosis is not fully understood, malabsorption, malnutrition, vitamin D deficiency, reduced levels of sexual hormones and alcohol toxicity appear to be some of the factors involved in altered bone metabolism [15,16,17,18,19]
The aim of the present work was to study the effect of low doses of IGF-I on bone in this animal model, by determining the following parameters: 1) bone weight, morphometry, densitometry and cortical thickness in histological preparations; 2) gene expression of IGF-I, and growth hormone (GH) and IGF-I receptors in bone; 3) gene and protein expression of key molecules involved in osteocyte or osteoblastic differentiation and activity, such as osteoprotegerin (OPG), sclerostin (SOST), insulin-like growth factor binding protein-5 (IGFBP-5), runt-related transcription factor 2 (RUNX2), calcitonin receptor (CTR) [22,23,24,25]; 4) gene and protein expressions related to osteoclastic activity or inhibition, such as insulin-like growth factor binding protein-4 (IGFBP-4), parathormone receptor-1 (PTHR1), receptor activator for nuclear factor κ B ligand (RANKL) [26,27,28,29,30]
Summary
Bone 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. 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. Bone is one of the major target organs for insulin-like growth factor I (IGF-I) [1,2,3,4], an anabolic hormone produced mainly by the liver upon growth hormone (GH) stimulation [5,6,7]. Liver cirrhosis is associated with osteopenia and low levels of IGF-I [8,9,10], constituting a well established condition of IGF-I deficiency [11,12]. The mechanisms of the beneficial actions of IGF-I replacement therapy on bone are not entirely known yet
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