Search Results
Search for other papers by A Gröne in
Google Scholar
PubMed
Search for other papers by L K McCauley in
Google Scholar
PubMed
Search for other papers by C C Capen in
Google Scholar
PubMed
Search for other papers by T J Rosol in
Google Scholar
PubMed
Abstract
The effect of humoral hypercalcaemia of malignancy (HHM) on parathyroid hormone/parathyroid hormonerelated protein (PTH/PTHrP) receptor expression was investigated in nude mice with subcutaneous transplantation of an adenocarcinoma line (CAC-8) which produces PTHrP. Serum calcium and PTHrP concentrations were analysed by colorimetric assay and a two-site IRMA respectively. Mice were hypercalcaemic (3·3 ±0·1 mmol/l) compared with non-tumour-bearing control mice (2·1 ± 0·1 mmol/l) and had elevated serum PTHrP concentrations (30·4 ±3·4 pmol/l) compared with non-tumour-bearing control mice (0·7 ±0·1 pmol/l. Lumbar vertebrae were analysed by histomorphometry. Tumourbearing mice had a significant (P<0·01) increase in resorptive perimeter, increased numbers of osteoclasts/mm endosteum and increased endosteal bone-forming perimeter. Total RNA was isolated from calvarium, humerus and kidney and analysed for PTH/PTHrP receptor expression by Northern blot analysis. There was no significant difference between PTH/PTHrP receptor mRNA expression in the kidneys and humeri of tumourbearing mice compared with non-tumour control mice, but a significant increase in PTH/PTHrP receptor expression in calvaria. Kidneys and vertebral bodies were stained for PTH/PTHrP receptor protein by immunohistochemistry. Renal proximal tubules (especially the basolateral regions) and endosteal osteoblasts of control and tumourbearing mice stained positive for PTH/PTHrP receptor. These results demonstrated that HHM induced by increased serum PTHrP concentrations did not result in down-regulation of PTH/PTHrP receptor mRNA or protein expression in vivo.
Journal of Endocrinology (1997) 153, 123–129
Search for other papers by T. Kurabayashi in
Google Scholar
PubMed
Search for other papers by T. Fujimaki in
Google Scholar
PubMed
Search for other papers by M. Yasuda in
Google Scholar
PubMed
Search for other papers by Y. Yamamoto in
Google Scholar
PubMed
Search for other papers by K. Tanaka in
Google Scholar
PubMed
ABSTRACT
This study was carried out (1) to compare the time-course of the change in bone metabolism in rats administered gonadotrophin-releasing hormone agonist (GnRHa) and bilaterally ovariectomized (OVX) rats and (2) to investigate the changes in bone metabolism after discontinuance of GnRHa.
Seventy female Sprague–Dawley rats, aged 90 days, were divided into four groups. Group 1 underwent a sham operation, group 2 was surgically ovariectomized and group 3 was given a GnRHa (leuprorelin acetate for depot suspension) s.c. injection every 30 days. Group 3 was further divided into three subgroups: rats were administered GnRHa for 12 months (GnRHa 12M), 6 months (GnRHa 6M) or 3 months (GnRHa 3M). Group 4 served as a basal control. The bone mineral density (BMD) of lumbar vertebrae and femoral bone, measured by dual-energy X-ray absorptiometry, and the serum bone metabolic parameters were determined every 45–90 days. The bone histomorphometry of lumbar vertebra was measured on days 180 and 360 after surgery.
GnRHa 12M rats showed significantly lower BMD of vertebrae and femoral bone, lower bone volume and higher bone turnover compared with sham-operated rats and those with secondary hyperparathyroidism on days 180 and 360. Their time-course for changes in bone metabolism was almost the same as that of OVX rats. GnRHa-discontinued rats showed a recovery of bone turnover. The recovery of BMD in GnRHa 6M rats was smaller than that of GnRHa 3M rats after GnRHa discontinuance. The bone volume for GnRHa 6M rats was significantly lower than that for GnRHa 3M on day 360.
Journal of Endocrinology (1993) 138, 115–125
Search for other papers by J Cornish in
Google Scholar
PubMed
Search for other papers by KE Callon in
Google Scholar
PubMed
Search for other papers by U Bava in
Google Scholar
PubMed
Search for other papers by C Lin in
Google Scholar
PubMed
Search for other papers by D Naot in
Google Scholar
PubMed
Search for other papers by BL Hill in
Google Scholar
PubMed
Search for other papers by AB Grey in
Google Scholar
PubMed
Search for other papers by N Broom in
Google Scholar
PubMed
Search for other papers by DE Myers in
Google Scholar
PubMed
Search for other papers by GC Nicholson in
Google Scholar
PubMed
Search for other papers by IR Reid in
Google Scholar
PubMed
Fat mass is an important determinant of bone density, but the mechanism of this relationship is uncertain. Leptin, as a circulating peptide of adipocyte origin, is a potential contributor to this relationship. Recently it was shown that intracerebroventricular administration of leptin is associated with bone loss, suggesting that obesity should be associated with low bone mass, the opposite of what is actually found. Since leptin originates in the periphery, an examination of its direct effects on bone is necessary to address this major discrepancy. Leptin (>10(-11) m) increased proliferation of isolated fetal rat osteoblasts comparably with IGF-I, and these cells expressed the signalling form of the leptin receptor. In mouse bone marrow cultures, leptin (>or=10(-11) m) inhibited osteoclastogenesis, but it had no effect on bone resorption in two assays of mature osteoclasts. Systemic administration of leptin to adult male mice (20 injections of 43 micro g/day over 4 weeks) reduced bone fragility (increased work to fracture by 27% and displacement to fracture by 21%, P<0.001). Changes in tibial histomorphometry were not statistically significant apart from an increase in growth plate thickness in animals receiving leptin. Leptin stimulated proliferation of isolated chondrocytes, and these cells also expressed the signalling form of the leptin receptor. It is concluded that the direct bone effects of leptin tend to reduce bone fragility and could contribute to the high bone mass and low fracture rates of obesity. When administered systemically, the direct actions of leptin outweigh its centrally mediated effects on bone, the latter possibly being mediated by leptin's regulation of insulin sensitivity.
Search for other papers by J Cornish in
Google Scholar
PubMed
Search for other papers by KE Callon in
Google Scholar
PubMed
Search for other papers by U Bava in
Google Scholar
PubMed
Search for other papers by DH Coy in
Google Scholar
PubMed
Search for other papers by TB Mulvey in
Google Scholar
PubMed
Search for other papers by MA Murray in
Google Scholar
PubMed
Search for other papers by GJ Cooper in
Google Scholar
PubMed
Search for other papers by IR Reid in
Google Scholar
PubMed
Adrenomedullin is a 52-amino acid peptide first described in a human phaeochromocytoma but since been found to be present in many tissues, including the vascular system and bone. Because of its structural similarity to amylin and calcitonin gene-related peptide, both of which have actions on bone cells, we have previously assessed the effects of adrenomedullin on the skeleton, and found that it increases osteoblast proliferation in vitro and bone formation following local injection in vivo. The present study carries this work forward by assessing the effects on bone of the systemic administration of a fragment of this peptide lacking the structural requirements for vasodilator activity. Two groups of 20 adult male mice received 20 injections of human adrenomedullin(27-52) 8.1 microg or vehicle over a 4-week period and bone histomorphometry and strength were assessed. In the tibia, adrenomedullin(27-52) produced increases in the indices of osteoblast activity, osteoid perimeter and osteoblast perimeter (P<0.05 for both using Student's t-test). Osteoclast perimeter was not affected. There was a 21% increase in cortical width and a 45% increase in trabecular bone volume in animals treated with adrenomedullin(27-52) (P<0.002 for both). Assessment of bone strength by three-point bending of the humerus showed both the maximal force and the displacement to the point of failure were increased in the animals treated with adrenomedullin(27-52) (P<0.03 for both). There was also a significant increase in the thickness of the epiphyseal growth plate. No adverse effects of the treatment were noted. It is concluded that adrenomedullin(27-52) acts as an anabolic agent on bone. These findings may be relevant to the normal regulation of bone mass and to the design of agents for the treatment of osteoporosis.
Search for other papers by Y Wang in
Google Scholar
PubMed
Search for other papers by T Yano in
Google Scholar
PubMed
Search for other papers by A Kikuchi in
Google Scholar
PubMed
Search for other papers by N Yano in
Google Scholar
PubMed
Search for other papers by H Matsumi in
Google Scholar
PubMed
Search for other papers by K Ando in
Google Scholar
PubMed
Search for other papers by Y Kasai in
Google Scholar
PubMed
Search for other papers by M Watanabe in
Google Scholar
PubMed
Search for other papers by R Okagaki in
Google Scholar
PubMed
Search for other papers by Y Osuga in
Google Scholar
PubMed
Search for other papers by Y Taketani in
Google Scholar
PubMed
The hypoestrogenic state induced by gonadotrophin-releasing hormone agonist (GnRHa) has been shown to be effective in the treatment of oestrogen-dependent disorders but to induce bone loss. Adding back low doses of oestrogen in GnRHa therapy has been proposed to prevent bone loss. The purpose of this study is to assess the efficacy of add-back therapy with different natural oestrogens such as oestrone (OE(1)), oestradiol (OE(2)) and oestriol (OE(3)). Three-month-old female rats (250 g) were subcutaneously administered microcapsules of leuprorelin acetate in doses of 1 mg/kg of body weight every 4 weeks. GnRHa therapy lasted 16 weeks, and pellets of OE(1), OE(2) or OE(3) (0.5 mg/pellet, 60 day release), as an add-back agent, were implanted at 8 weeks of treatment. At the end of treatment, GnRHa alone decreased bone mineral density of the femur and lumbar vertebrae, and increased serum levels of bone metabolic markers such as alkaline phosphatase and osteocalcin levels. As for cancellous bone histomorphometry, GnRHa decreased bone volume while it increased osteoid volume, osteoid surface, eroded surface, mineral apposition rate and bone formation rate. All the oestrogens tested prevented these changes caused by GnRHa therapy. GnRHa induced a significant increase in body weight and a marked reduction in uterine weight, which was not observed in OE(1) or OE(2) add-back group. Body weight and uterine weight of the OE(3) add-back group were the same as those of the GnRHa group. These findings indicate that GnRHa induces high turnover bone loss which can be prevented by concomitant administration of natural oestrogens such as OE(1), OE(2) and OE(3) to the same extent. In addition, OE(3) is unique in that it is much less effective than OE(1) and OE(2) in blocking body weight gain and in promoting growth of uterine tissues. Because of its tissue-selective actions, OE(3) could be considered as one of the most appropriate oestrogens used for GnRHa add-back therapy.
Search for other papers by C Martel in
Google Scholar
PubMed
Search for other papers by A Sourla in
Google Scholar
PubMed
Search for other papers by G Pelletier in
Google Scholar
PubMed
Search for other papers by C Labrie in
Google Scholar
PubMed
Search for other papers by M Fournier in
Google Scholar
PubMed
Search for other papers by S Picard in
Google Scholar
PubMed
Search for other papers by S Li in
Google Scholar
PubMed
Search for other papers by M Stojanovic in
Google Scholar
PubMed
Search for other papers by F Labrie in
Google Scholar
PubMed
In order to assess the relative roles of the androgenic and/or estrogenic components in the stimulatory effect of dehydroepiandrosterone (DHEA) on bone mineral content (BMC) and density (BMD), ovariectomized (OVX) female rats received DHEA administered alone or in combination with the antiandrogen flutamide (FLU) or the antiestrogen EM-800 for 12 months. We also evaluated, for comparison, the effect of estradiol (E2) and dihydrotestosterone (DHT) constantly released by Silastic implants as well as medroxyprogesterone acetate (MPA) released from poly(lactide-co-glycolide) microspheres. Femoral BMD was decreased by 11% 1 year after OVX, but treatment of OVX animals with DHEA increased BMD to a value 8% above that of intact animals. The administration of FLU reversed by 76% the stimulatory effect of DHEA on femoral BMD and completely prevented the stimulatory effect of DHEA on total body and lumbar spine BMD. Similar results were obtained for BMC. On the other hand, treatment with the antiestrogen EM-800 did not reduce the action of DHEA on BMD or BMC. At the doses used, MPA, E2 and DHT increased femoral BMD, but to a lesser degree than observed with DHEA. Bone histomorphometry measurements were also performed. While DHEA treatment partially reversed the marked inhibitory effect of OVX on the tibial trabecular bone volume, the administration of FLU inhibited by 51% (P < 0.01) the stimulatory effect of DHEA on this parameter. The addition of EM-800 to DHEA, on the other hand, increased trabecular bone volume to a value similar to that of intact controls. DHEA administration markedly increased trabecular number while causing a marked decrease in the intertrabecular area. The above stimulatory effect of DHEA on trabecular number was reversed by 54% (P < 0.01) by the administration of FLU, which also reversed by 29% the decrease in intertrabecular area caused by DHEA administration. On the other hand, the addition of EM-800, while further decreasing the intertrabecular space achieved by DHEA treatment, also led to a further increase in trabecular number to a value not significantly different from that of intact control animals, suggesting an additional effect of EM-800 over that achieved by DHEA. Treatment with DHEA caused a 4-fold stimulation of serum alkaline phosphatase, a marker of bone formation, while the urinary excretion of hydroxyproline, a marker of bone resorption, was decreased by DHEA treatment. Treatment with DHEA and DHEA + EM-800 decreased serum cholesterol levels by 22 and 65% respectively, while the other treatments had no significant effect on this parameter. The present data indicate that the potent stimulatory effect of DHEA on bone in the rat is mainly due to the local formation of androgens in bone cells and their intracrine action in osteoblasts.
Search for other papers by J. Verhaeghe in
Google Scholar
PubMed
Search for other papers by A. M. H. Suiker in
Google Scholar
PubMed
Search for other papers by W. J. Visser in
Google Scholar
PubMed
Search for other papers by E. Van Herck in
Google Scholar
PubMed
Search for other papers by R. Van Bree in
Google Scholar
PubMed
Search for other papers by R. Bouillon in
Google Scholar
PubMed
ABSTRACT
Spontaneously diabetic BB rats have a markedly depressed longitudinal bone growth and bone formation/turnover. In this study, male diabetic BB rats were infused intraperitoneally or subcutaneously for 2 weeks with hormones that are believed to stimulate skeletal growth and/or trabecular bone formation: insulin (3 or 4 U/day), human GH (hGH; 400 mU/day), recombinant human insulin-like growth factor-I (rhIGF-I; 300 or 600 μg/day) and testosterone (80 μg/100 g body weight per day).
Saline-treated diabetic BB rats had decreased plasma concentrations of IGF-I and osteocalcin (OC) (OC, 3·7 ±0·3 vs 13·1 ± 0·8 (s.e.m.) nmol/l in controls); bone histomorphometry showed decreased epiphyseal width, osteoblast surface (0·04±0·04 vs 1·5±0·3%) and osteoid surface, and mineral apposition rate (MAR) (1·8±0·5 vs 7·9±0·6 μm/day).
Testosterone and hGH infusions had no effect on weight loss or on decreased skeletal growth and bone formation of diabetic rats, nor did they increase plasma IGF-I concentrations. Insulin infusions into diabetic rats resulted in hyperinsulinaemia and accelerated weight gain. The epiphyseal width, osteoblast/osteoid surfaces and OC levels of insulin-treated rats were normalized or stimulated well above control values (osteoblast surface, 4·3 ±0·8%; plasma OC, 16·1 ± 1·4 nmol/l); the MAR (4·0 ± 0·9 μm/day) was only partly corrected after the 2-week infusion. Infusions of rhIGF-I into diabetic rats doubled but did not restore plasma IGF-I levels to normal; weight gain, however, was similar to that in control rats. IGF-I treatment had no effect on epiphyseal width, osteoblast/osteoid surfaces and OC concentrations, but improved the decreased MAR (4·6±1·2 μm/day).
These results indicate (1) that the decreased epiphyseal width and osteoblast recruitment of diabetic BB rats are directly related to their insulin deficiency, and (2) that IGF-I, administered systemically, corrects, in part, the decreased MAR in diabetes, suggesting a role in osteoblast function and/or mineralization.
Journal of Endocrinology (1992) 134, 485–492
Search for other papers by Stefano Zanotti in
Google Scholar
PubMed
Search for other papers by Lisa Stadmeyer in
Google Scholar
PubMed
Search for other papers by Anna Smerdel-Ramoya in
Google Scholar
PubMed
Search for other papers by Deena Durant in
Google Scholar
PubMed
Department of Research, The University of Connecticut School of Medicine, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, Connecticut 06105-1299, USA
Search for other papers by Ernesto Canalis in
Google Scholar
PubMed
Static and dynamic histomorphometry was carried out on transgenic mice and wild type littermate controls and Cebpb −/− mice and wild type, sex and age, matched controls of the same genetic composition. Mice were injected with calcein, 20 mg/kg, and
Search for other papers by H H Farman in
Google Scholar
PubMed
Search for other papers by K L Gustafsson in
Google Scholar
PubMed
Search for other papers by P Henning in
Google Scholar
PubMed
Search for other papers by L Grahnemo in
Google Scholar
PubMed
Search for other papers by V Lionikaite in
Google Scholar
PubMed
Search for other papers by S Movérare-Skrtic in
Google Scholar
PubMed
Search for other papers by J Wu in
Google Scholar
PubMed
Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
Search for other papers by H Ryberg in
Google Scholar
PubMed
Search for other papers by A Koskela in
Google Scholar
PubMed
Search for other papers by J Tuukkanen in
Google Scholar
PubMed
The Long Beach VA Medical Center, Long Beach, California, USA
Search for other papers by E R Levin in
Google Scholar
PubMed
Search for other papers by C Ohlsson in
Google Scholar
PubMed
Search for other papers by M K Lagerquist in
Google Scholar
PubMed
at a distance of 5 μm caudal of the lower end of the pedicles and extending 225 µm in the caudal direction. Histomorphometric analyses Bone histomorphometry was applied to analyze static and dynamic parameters in trabecular and cortical bone
Search for other papers by Bernardo Nuche-Berenguer in
Google Scholar
PubMed
Search for other papers by Daniel Lozano in
Google Scholar
PubMed
Search for other papers by Irene Gutiérrez-Rojas in
Google Scholar
PubMed
Search for other papers by Paola Moreno in
Google Scholar
PubMed
Search for other papers by María L Mariñoso in
Google Scholar
PubMed
Search for other papers by Pedro Esbrit in
Google Scholar
PubMed
Search for other papers by María L Villanueva-Peñacarrillo in
Google Scholar
PubMed
vertebrae were also collected, stripped of soft tissue, and kept in 70% ethanol for the analysis of bone mineral density (BMD), bone mineral content (BMC), and/or bone histomorphometry. Animal housing and protocols were approved by the Animal Use Committee
