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J H Tobias, T J Chambers and A Gallagher

Abstract

Although hormone replacement therapy can prevent postmenopausal bone loss, it does not restore bone mass to normal in patients with established osteoporosis. This might reflect a failure to reproduce certain aspects of gonadal function. One method of investigating this possibility would be to examine the effect of ovarian transplantation on the skeleton of osteopaenic ovariectomized rats. However, ovarian transplantation may not fully restore ovarian function to normal, and it is not known whether transplanted ovaries reproduce the action of native ovaries on the skeleton. Therefore, we investigated whether renal capsular or subcutaneous ovarian transplants prevent the effects of ovariectomy on histomorphometric indices of rat tibiae over 44 days. Daily vaginal smears showed that oestrous cycles returned in all but two of 25 animals receiving ovarian transplants. We found that ovarian transplantation prevented the reduction in cancellous bone volume following ovariectomy. While trabecular number was reduced in ovariectomized animals receiving renal capsular ovarian transplants compared to intact animals, trabecular thickness was increased in both transplant groups. Ovarian transplantation also prevented the increase in cancellous and cortical bone formation, cancellous bone resorption and longitudinal growth rate caused by ovariectomy. We conclude that restoration of ovarian function by ovarian transplantation largely prevents the effects of ovariectomy on histomorphometric indices of rat tibiae, suggesting that transplanted ovaries can substitute for the action of native ovaries on the skeleton.

Journal of Endocrinology (1994) 142, 187–192

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H Uemura, T Yasui, M Kiyokawa, A Kuwahara, H Ikawa, T Matsuzaki, M Maegawa, H Furumoto and M Irahara

Pregnancy and lactation induce dynamic changes in maternal bone and calcium metabolism. A novel cytokine termed osteoprotegerin (OPG)/osteoclastogenesis-inhibitory factor (OCIF) was recently isolated; this cytokine inhibits osteoclast maturation. To define the effects of pregnancy and lactation on circulating OPG/OCIF in mothers, we studied the changes in the levels of OPG/ OCIF as well as those of calcium-regulating hormones and biochemical markers of bone turnover in the maternal circulation during pregnancy (at 8-11 weeks, at 22-30 weeks, at 35-36 weeks and immediately before delivery) and lactation (at 4 days and at 1 month postpartum). Serum intact parathyroid hormone levels did not change and were almost within the normal range in this period. In contrast, serum 1,25-dihydroxyvitamin D levels increased with gestational age and were above the normal range during pregnancy. After delivery, they fell rapidly and significantly (P<0.01) to the normal range. The levels of serum bone-specific alkaline phosphatase, one of the markers of bone formation, increased with gestational age. After delivery, these levels were further increased at 1 month postpartum. The levels at 1 month postpartum were significantly higher than those at 8-11 and 22-30 weeks of pregnancy (P<0.01 and P<0.05 respectively). The levels of serum C-terminal telopeptides of type I collagen, one of the markers of bone resorption, did not change during pregnancy. After delivery, they rapidly and significantly (P<0.01) rose at 4 days postpartum, and had then fallen by 1 month postpartum. Circulating OPG/OCIF levels gradually increased with gestational age and significantly (P<0.01) increased immediately before delivery to 1.40+/-0.53 ng/ml (means+/-S.D.) compared with those in the non-pregnant, non-lactating controls (0.58+/-0.11 ng/ml). After delivery, they fell rapidly to 0.87+/-0.27 ng/ml at 4 days postpartum and had fallen further by 1 month postpartum. These results suggest that the fall in OPG/OCIF levels may be partially connected with the marked acceleration of bone resorption after delivery.

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C Martel, A Sourla, G Pelletier, C Labrie, M Fournier, S Picard, S Li, M Stojanovic and F Labrie

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.

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N Loveridge, C Farquharson, R Palmer, G E Lobley and D J Flint

Abstract

The control of longitudinal growth is poorly understood but GH is considered to be one of the major hormones regulating postnatal growth. However, there is dispute as to whether it has a direct or indirect action. To study the role of GH we used a polyclonal antiserum to rat GH and investigated changes in cell proliferation and enzyme activities associated with bone formation and resorption during longitudinal growth. IGF-I levels were measured by two independent RIAs, DNA synthesis by bromodeoxyuridine incorporation followed by immunocytochemistry and enzyme activities were quantified in situ by microdensitometry.

After 1 day the percentage of chondrocytes undergoing DNA synthesis within the proliferative zone was reduced but no other parameters were affected. By day 4 the labelling index was the same as in pair-fed animals but the number of chondrocytes synthesising DNA was reduced as was the total width of the growth plate and that of the proliferative zone. Alkaline phosphatase (associated with mineralisation) was unchanged but glucose 6-phosphate dehydrogenase activity (associated with cell proliferation) was decreased. Osteoclastic tartrate-resistant acid phosphatase activity (associated with bone resorption) was also significantly reduced. Similar changes were apparent after 10 days. At no time was the circulating level of IGF-I decreased.

These data suggest that, during longitudinal growth, GH affects the number of proliferating chondrocytes but not the percentage of cells undergoing DNA synthesis, indicating that its primary role may be on the commitment of prechondrocytes to a proliferative state. Furthermore, while GH does not seem to have any effect on skeletal mineralisation it may stimulate osteoclastic resorption of the primary spongiosa.

Journal of Endocrinology (1995) 146, 55–62

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J Svensson, S Lall, SL Dickson, BA Bengtsson, J Romer, I Ahnfelt-Ronne, C Ohlsson and JO Jansson

Growth hormone (GH) is of importance for normal bone remodelling. A recent clinical study demonstrated that MK-677, a member of a class of GH secretagogues (GHSs), increases serum concentrations of biochemical markers of bone formation and bone resorption. The aim of the present study was to investigate whether the GHSs, ipamorelin (IPA) and GH-releasing peptide-6 (GHRP-6), increase bone mineral content (BMC) in young adult female rats. Thirteen-week-old female Sprague-Dawley rats were given IPA (0.5 mg/kg per day; n=7), GHRP-6 (0.5 mg/kg per day; n=8), GH (3.5 mg/kg per day; n=7), or vehicle administered continuously s.c. via osmotic minipumps for 12 weeks. The animals were followed in vivo by dual X-ray absorptiometry (DXA) measurements every 4th week. After the animals were killed, femurs were analysed in vitro by mid-diaphyseal peripheral quantitative computed tomography (pQCT) scans. After this, excised femurs and vertebrae L6 were analysed by the use of Archimedes' principle and by determinations of ash weights. All treatments increased body weight and total tibial and vertebral BMC measured by DXA in vivo compared with vehicle-treated controls. However, total BMC corrected for the increase in body weight (total BMC:body weight ratio) was unaffected. Tibial area bone mineral density (BMD, BMC/area) was increased, but total and vertebral area BMDs were unchanged. The pQCT measurements in vitro revealed that the increase in the cortical BMC was due to an increased cross-sectional bone area, whereas the cortical volumetric BMD was unchanged. Femur and vertebra L6 volumes were increased but no effect was seen on the volumetric BMDs as measured by Archimedes' principle. Ash weight was increased by all treatments, but the mineral concentration was unchanged. We conclude that treatment of adult female rats with the GHSs ipamorelin and GHRP-6 increases BMC as measured by DXA in vivo. The results of in vitro measurements using pQCT and Archimedes' principle, in addition to ash weight determinations, show that the increases in cortical and total BMC were due to an increased growth of the bones with increased bone dimensions, whereas the volumetric BMD was unchanged.

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J Gebken, A Feydt, J Brinckmann, H Notbohm, PK Muller and B Batge

High concentrations of transforming growth factor b (TGF-beta) are found in the bone matrix, reflecting a pivotal role of this growth factor in the coupling of bone resorption and formation. TGF-beta strongly stimulates the synthesis of extracellular matrix proteins, but in vitro studies show an inhibitory effect on the final mineralization process, which in vivo occurs despite high concentrations of TGF-beta. Little is known about how bone-forming cells respond to different concentrations of TGF-beta and if they can transiently adapt receptor numbers in order to modulate cellular activity. Against this background, we studied the cell-surface expression of TGF-beta receptors (TbetaR) I, II and III (betaglycan) on human osteoblast-like cells from adult donors, and examined the TbetaR presentation on these cells after a preceding exposure to TGF-beta1. Affinity crosslinking studies with disuccinimidylsuberate showed the presence of all three receptor types. Preincubation with TGF-beta1 markedly reduced 125I-TGF-beta1 binding in a time-dependent and dose-dependent manner and revealed a 95% reduction after an 18-h preincubation with 200 pM TGF-beta1. In parallel, Scatchard analysis showed that the binding affinity did not change as a consequence of TGF-beta1 preincubation. Immunoblotting analyses revealed an almost complete disappearance of immunoreactive TbetaR-II and TbetaR-III proteins after a 24-h preincubation with TGF-beta1. Using semi-quantitative reverse transcription PCR, no effect of TGF-beta1 on the expression of TbetaR-II mRNA was observed. These studies demonstrate a ligand-induced downregulation of TbetaRs-II and -III on human osteoblast-like cells, without any evidence for recovery within the first 24 h, both in the presence and after the removal of the ligand. The underlying mechanism appears to be based on post-transcriptional events. The results suggest that high concentrations of active TGF-beta1 decrease the responsiveness of osteoblasts towards this growth factor.

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I. R. Dickson and P. M. Maher

ABSTRACT

When growth cartilage from rachitic chicks was cultured in the presence of the calcium-regulating hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), collagen resorption was increased and collagen synthesis decreased compared to control cultures containing no hormone. The minimum concentration of the hormone that caused a statistically significant inhibition of collagen synthesis was 10 −8 mol/l. Collagen synthesis by growth cartilage from normal chicks was also reduced by 1,25-(OH)2D3, showing that it was not an abnormal response of vitamin D-depleted tissue. 25-Hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 also inhibited collagen synthesis by cultures of growth cartilage but only at higher metabolite concentrations. 1,25-Dihydroxyvitamin D3 (10−7 mol/l) did not significantly inhibit collagen synthesis by cultures of articular fibrocartilage and of sternal cartilage, tissues that do not calcify physiologically. The minimum concentration of 1,25-(OH)2D3 (10−9 mol/l) necessary to cause decreased collagen synthesis by embryonic chick calvaria was lower than the value obtained with growth cartilage; this suggests that bone cells may be more sensitive to the hormone in this respect than are growth cartilage chondrocytes. These findings provide evidence of a direct role of 1,25-(OH)2D3 in the control of endochondral bone formation which is consistent with its primary role in the maintenance of plasma calcium homeostasis.

J. Endocr. (1985) 105, 79–85

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R S Birnbaum, R R Bowsher and K M Wiren

Abstract

IGF-I and -II have potent effects on proliferation and differentiation of osteoblasts in vitro. These cells secrete both IGFs and expression of these peptides is regulated by several of the hormones and growth factors that promote bone resorption and/or formation. However, the physiological role(s) of IGFs in the remodelling process of adult bone is still unclear. Some confusion may arise from results influenced, in part, by differences in the state of osteoblast development of in vitro cultures. Several laboratories have demonstrated that murine osteoblast cultures progress from proliferating preosteoblasts, to mature differentiated osteoblasts that form an extracellular matrix, to cultures that form a mineralized matrix. We have recently documented changes in IGF-binding protein expression and secretion in these cultures. To complement and extend this work, we have examined IGF-I expression and secretion and IGF-II expression during in vitro osteoblast development.

Steady-state mRNA levels of both IGF-I and -II increased from the earliest time examined, day 5 in culture, to a maximum at day 11 and, thereafter, declined. IGF-I secreted into the medium also changed in a biphasic manner, but IGF-II could not be quantitated due to the sensitivity of our assay. Secretion of IGF-I was lowest between days 8 and 14. IGF-I secretion on day 5 was significantly greater than day 8. Similarly, IGF-I secretion from day 17 to 26 was also greater than observed for days 8 to 14. If differentiation of the cells was inhibited, this late rise in IGF-I secretion was abolished. We conclude that IGF-I is an autocrine mitogen of the proliferating preosteoblasts. Further, we also suggest that the rise in IGF-I secretion, late in osteoblast development, may lead to sequestration of this mitogen in the extracellular matrix for release during a subsequent remodelling cycle.

Journal of Endocrinology (1995) 144, 251–259

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Colin Farquharson and Katherine Staines

addition to providing a general review of endochondral ossification and bone formation and resorption, have focussed on some of the recent advances in chondrocyte, osteoblast and osteoclast biology. In the first thematic review, Mackie et al . (2011

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Muneaki Ishijima, Kunikazu Tsuji, Susan R Rittling, Teruhito Yamashita, Hisashi Kurosawa, David T Denhardt, Akira Nifuji, Yoichi Ezura and Masaki Noda

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