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Osteopenia has been ascribed to diabetics without residual insulin secretion and high insulin requirement. However, it is not known if this is partially due to disturbances in the IGF system, which is a key regulator of bone cell function. To address this question, we performed a cross-sectional study measuring serum levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, IGFBP-4 and IGFBP-5 by specific immunoassays in 52 adults with Type 1 (n=27) and Type 2 (n=25) diabetes mellitus and 100 age- and sex-matched healthy blood donors. In the diabetic patients, we further determined serum levels of proinsulin, intact parathyroid hormone (PTH), 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and several biochemical bone markers, including osteocalcin (OSC), bone alkaline phosphatase (B-ALP), carboxy-terminal propeptide of type I procollagen (PICP), and type I collagen cross-linked carboxy-terminal telopeptide (ICTP). Urinary albumin excretion was ascertained as a marker of diabetic nephropathy. Bone mineral density (BMD) of hip and lumbar spine was determined by dual-energy X-ray absorptiometry. Data are presented as means+/-s.e.m. Differences between the experimental groups were determined by performing a one-way analysis of variance (ANOVA), followed by Newman-Keuls test. Correlations between variables were assessed using univariate linear regression analysis and partial correlation analysis. Type 1 diabetics showed significantly lower IGF-I (119+/-8 ng/ml) and IGFBP-3 (2590+/-104 ng/ml) but higher IGFBP-1 levels (38+/-10 ng/ml) compared with Type 2 patients (170+/-13, 2910+/-118, 11+/-3 respectively; P<0.05) or healthy controls (169+/-5, 4620+/-192, 3.5+/-0.4 respectively; P<0.01). IGFBP-5 levels were markedly lower in both diabetic groups (Type 1, 228+/-9; Type 2, 242+/-11 ng/ml) than in controls (460+/-7 ng/ml,P<0. 01), whereas IGFBP-4 levels were similar in diabetics and controls. IGF-I correlated positively with IGFBP-3 and IGFBP-5 and negatively with IGFBP-1 and IGFBP-4 in all subjects. Type 1 patients showed a lower BMD of hip (83+/-2 %, Z-score) and lumbar spine (93+/-2 %) than Type 2 diabetics (93+/-5 %, 101+/-5 % respectively), reaching significance in the female subgroups (P<0.05). In Type 1 patients, BMD of hip correlated negatively with IGFBP-1 (r=-0.34, P<0.05) and IGFBP-4 (r=-0.3, P<0.05) but positively with IGFBP-5 (r=0.37, P<0. 05), which was independent of age, diabetes duration, height, weight and body mass index, as assessed by partial correlation analysis. Furthermore, biochemical markers indicating bone loss (ICTP) and increased bone turnover (PTH, OSC) correlated positively with IGFBP-1 and IGFBP-4 but negatively with IGF-I, IGFBP-3 and IGFBP-5, while the opposite was observed with bone formation markers (PICP, B-ALP) and vitamin D3 metabolites. In 20 Type 2 patients in whom immunoreactive proinsulin could be detected, significant positive correlations were found between proinsulin and BMD of hip (r=0.63, P<0.005), IGF-I (r=0.59, P<0.01) as well as IGFBP-3 (r=0.49, P<0.05). Type 1 and Type 2 patients with macroalbuminuria showed a lower BMD of hip, lower IGFBP-5 but higher IGFBP-4 levels, suggesting that diabetic nephropathy may contribute to bone loss by a disturbed IGF system. In conclusion, the findings of this study support the hypothesis that the imbalance between individual IGF system components and the lack of endogenous proinsulin may contribute to the lower BMD in Type 1 diabetics.
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2-Hydroxyestrone (2-OHE(1)) and 16alpha-hydroxyestrone (16alpha-OHE(1)) have been reported to be risk factors for negative bone balance and breast cancer, respectively. The roles of these two metabolites of estrone as estrogen agonists or antagonists with respect to estrogen target tissues, or both, are poorly defined. The purpose of this study was to characterize metabolite and tissue-specific differences between the actions of hydroxylated estrones on selected reproductive and non-reproductive estrogen target tissues in growing rats. First, the effects of ovariectomy were determined. Ovariectomy had the expected effects, including increases in all dynamic bone measurements at the proximal tibial epiphysis, without induction of bone loss. Second, ovariectomized growing rats were continuously treated for 3 weeks with 2-OHE(1), 16alpha-OHE(1), 17beta-estradiol (E(2)), a combination of E(2) and 2-OHE(1) (E(2)+2-OHE(1)), or a combination of E(2) and 16alpha-OHE(1) (E(2)+16alpha-OHE(1)), using controlled release subcutaneous implanted pellets containing 5 mg 2-OHE(1), 5 mg 16alpha-OHE(1), 0.05 mg E(2) or placebo. E(2) reduced body weight gain and radial and longitudinal bone growth as well as indices of cancellous bone turnover, and increased serum cholesterol, uterine wet weight and epithelial cell height, and proliferative cell nuclear antigen labeling in mammary gland. The hydroxylated estrones did not alter uterine wet weight and 16alpha-OHE(1) antagonized the E(2)-stimulated increase in epithelial cell height. 2-OHE(1) had no effect on cortical bone, whereas 16alpha-OHE(1) was an estrogen agonist with respect to all cortical bone measurements. 16alpha-OHE(1) also behaved as an estrogen agonist with respect to serum cholesterol and cancellous bone measurements. 2-OHE(1) had no effect on most E(2)-regulated indices of cancellous bone growth and turnover, but was a weak estrogen agonist with respect to mineral apposition rate and bone formation rate. Neither estrogen metabolite influenced body weight gain. Third, weanling rats were treated for 1 week with vehicle, E(2) (200 microg/kg per day) or 16alpha-OHE(1) (30, 100, 300, 1000 and 3000 microg/kg per day) to confirm uterotropic effects of daily subcutaneous (s.c.) administration of 16alpha-OHE(1). 16alpha-OHE(1) increased uterine weight in a dose-response manner to values that did not differ from rats treated with E(2). We conclude that the estrogen metabolites 2-OHE(1) and 16alpha-OHE(1) have target tissue-specific biological activities which differ from one another as well as from E(2). These findings add further support to the concept that there are several classes of estrogens with distinct biological activities. Furthermore, differences in the route of administration could influence the tissue specificity of estrogen metabolites.
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‘female’ estrogen action on periosteal bone formation. However, particularly in men, the mechanism of action of sex steroids on bone growth appears considerably more complex. Testosterone, the main circulating androgen in males, not only activates the
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, USA
Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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reported that OPN is necessary for unloading-induced enhancement of bone resorption and suppression of bone formation in vivo ( Ishijima et al. 2001 , 2002 ). These data suggest that OPN plays a key role in conveying the effect of mechanical stress
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control and depends on a tight integration of cellular events within the skeleton and within the systems that deliver and accumulate mineral for hydroxyapatite formation ( Karsenty 2003 ). With few exceptions, bone formation is dependent on the development
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Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA
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Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA
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ob/ob and WT mice vary depending upon skeletal site and age. Leptin treatment in leptin-deficient mice normalizes bone volume and microarchitecture ( Iwaniec et al . 2007 ) by increasing bone formation ( Steppan et al . 2000 , Hamrick et al
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reflect those in human bone tissue. Bone turnover markers and circulating sclerostin levels Multiple studies in humans have found that serum markers of bone formation and resorption are reduced in diabetic individuals vs non-diabetic controls
Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK
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Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK
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Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK
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Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK
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Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK
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Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK
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Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK
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leptin receptor expression ( db/db genotype) exhibit a markedly elevated bone mass with increased mineralization and bone formation rate compared with wild-type mice. Intracerebroventricular (i.c.v) infusion of leptin in the ob/ob mice was shown to
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Harvard Medical School, Boston, Massachusetts, USA
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could lead to a relative increase in fat vs bone cells ( Thomas et al. 1999 ). Secondly, leptin replacement in hypoleptinemia decreases skeletal fragility in animal models ( Cornish et al . 2002 ) and increases bone formation markers in humans ( Welt
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by the osteoblast as a pre–pro-molecule and is commonly used as a serum marker of bone formation ( Brown et al . 1984 ). OCN exists in the general circulation in fully carboxylated, partially carboxylated and completely uncarboxylated forms
