Abstract
Insulin-dependent diabetes mellitus (IDDM) is known to be associated with an increased risk of osteopenia. However, the cellular and molecular mechanisms for IDDM-induced alterations of the bone are not well understood. The effects of IDDM on bone metabolism were investigated using rats rendered diabetic by an injection of streptozotocin (STZ). After 4 weeks, the diabetic rats exhibited bone loss, low levels of osteocalcin, insulin-like growth factor-I (IGF-I) and bone alkaline phosphatase (ALP) activity with normal levels of bone tartrate-resistant acid phosphatase (TRAP) and cathepsin K activity, and urinary excretion of deoxypyridinoline (Dpd). Histological analysis showed a decrease in the number of osteoblasts with a normal number of osteoclasts in the metaphysis of the proximal tibia. The decreased expression of ALP, osteoclacin and collagen mRNA was associated with a decrease in the expression of runt-related transcription factor 2 (Runx2), Osterix and distal-less homeobox 5 (Dlx5) and an unaltered expression of bone morphogenic protein-2 (BMP2). The protein levels of Runx2, phosphorylated glycogen synthase kinase 3β (GSK3β), active β-catenin and β-catenin decreased. The activation of Akt was inhibited. The mRNA and protein levels of sclerosteosis (Sost) and Dickkopf 1 (Dkk1), inhibitors of Wnt signaling, increased. The mRNA expression of IGF-I and the IGF-I receptor (IGF-IR) was suppressed. These changes observed in the bone of diabetic rats were reversed by treatment with insulin, but not by normalization of the circulating IGF-I levels by treatment with IGF-I. These results suggest that insulin-deficiency in IDDM decreases osteoblastogenesis associated with inhibition of Wnt signaling through the increased expression of Sost and Dkk1 and the inhibition of Akt activation.
MeSH terms
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Acid Phosphatase / metabolism
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Alkaline Phosphatase / metabolism
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Amino Acids / urine
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Animals
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Bone Morphogenetic Protein 2 / genetics
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Bone Morphogenetic Protein 2 / metabolism
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Bone Morphogenetic Proteins / genetics*
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Bone Morphogenetic Proteins / metabolism
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Cathepsin K / metabolism
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Core Binding Factor Alpha 1 Subunit / genetics
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Core Binding Factor Alpha 1 Subunit / metabolism
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Type 1 / metabolism*
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Female
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Genetic Markers / genetics*
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinase 3 beta
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Insulin-Like Growth Factor I / metabolism
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Intercellular Signaling Peptides and Proteins / genetics*
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Intercellular Signaling Peptides and Proteins / metabolism
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Isoenzymes / metabolism
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Osteoblasts / cytology
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Osteoblasts / metabolism
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Osteocalcin / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism*
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Rats
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Rats, Wistar
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Signal Transduction
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Tartrate-Resistant Acid Phosphatase
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Wnt Proteins / antagonists & inhibitors
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Wnt Proteins / metabolism*
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beta Catenin / metabolism
Substances
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Amino Acids
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Bmp2 protein, rat
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins
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Core Binding Factor Alpha 1 Subunit
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Distal-less homeobox proteins
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Dkk1 protein, rat
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Genetic Markers
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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Isoenzymes
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Runx2 protein, rat
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Sost protein, rat
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Transcription Factors
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Wnt Proteins
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beta Catenin
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Osteocalcin
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Insulin-Like Growth Factor I
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deoxypyridinoline
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Alkaline Phosphatase
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Cathepsin K