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Dipartimento di Scienze e Tecnologie Biomediche, Azienda Ospedaliero-Universitaria ‘S Maria della Misericordia’ Udine, Dipartimento di Ricerche Mediche e Morfologiche, Dipartimento di Medicina Interna, Dipartimento di Scienze Cliniche, Dipartimento di Scienze Farmacobiologiche, Università di Udine, Piazzale Kolbe 1, 33100 Udine, Italy
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periostin. It is a mesenchyme-specific gene product, originally identified as a gene expressed in mouse osteoblasts ( Takeshita et al . 1993 ), which acts as an adhesion molecule during bone formation and supports osteoblastic cell line attachment and
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ABSTRACT
We have previously demonstrated that administration of oestrogen, at doses sufficient to raise serum concentrations to those seen in late pregnancy, increases trabecular bone formation in the metaphysis of adult rats. To determine whether prostaglandins (PGs), which have been shown to induce osteogenesis in vivo, play a role in the induction of bone formation by oestrogen, 13-week-old female rats were given daily doses of 4 mg 17β-oestradiol (OE2)/kg for 17 days, alone or with indomethacin (1 mg/kg). The rats were also given double fluorochrome labels and at the end of the experiment tibias were subjected to histomorphometric assessment. Treatment with OE2 suppressed longitudinal bone growth and increased uterine wet weight, as expected, and neither response was affected by indomethacin. Oestrogen also induced a threefold increase in trabecular bone formation in the proximal tibial metaphysis, which resulted in a substantial increase in trabecular bone volume. As previously observed, the increase in bone formation was predominantly due to an increase in osteoblast recruitment (as judged by an increase in the percentage of bone surface showing double fluorochrome labels), with only a minor increase in the activity of mature osteoblasts (as judged by the mineral apposition rate). Indomethacin abolished the increase in osteoblastic recruitment, but the activity of mature osteoblastic cells remained high. The bone formation rate and bone volume remained similar to controls. The results suggest that PG production may be necessary for the increased osteoblastic recruitment induced by oestrogen, but not to mediate the effects of oestrogen on the activity of mature osteoblasts.
Journal of Endocrinology (1992) 133, 189–195
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SUMMARY
Pure calcium deficiency produces osteoporosis, or bone atrophy, in rats, while vitamin D deficiency as well as calcium deficiency leads to osteomalacia, or thin bones with wide osteoid seams. The retention of a dose of strontium in the osteoporotic rats is greater than normal, and this indicates rapid bone formation. The immediate cause of the bone thinning must therefore be an increase in the rate of bone resorption, contrary to the classical concepts of osteoporosis.
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ABSTRACT
We have previously found that administration of oestradiol-17β (OE2) to intact adult female rats of 19 days stimulates cancellous bone formation. However, this effect is not observed following longer periods of OE2 treatment, suggesting that the responsiveness of the skeleton to oestrogen's anabolic action is reduced after prolonged administration. A possible explanation for this is that oestrogen also suppresses bone resorption, which is an important stimulus for bone formation. We therefore investigated the effect of omitting OE2 for short periods, on the proximal tibial metaphysis of intact female rats. We found that, unlike continuous treatment with OE2 (40 pg/kg) for 56 days, omission of OE2 for 4 days out of every 20 was associated with a significant increase in cancellous bone volume. Although continuous and intermittent OE2 were both associated with a reduction in osteoclast surface, a decrease in the proportion of double fluorochrome-labelled surface was only seen after continuous OE2 treatment. We then studied the effects of longer periods of OE2 omission by giving OE2 (40 pg/kg) for three repeated cycles of: (1) OE2 for 16 days/vehicle for 4 days, (2) OE2 for 12 days/vehicle for 8 days, (3) OE2 for 8 days/vehicle for 12 days, or (4) OE2 for 4 days/vehicle for 16 days. We found a significant increase in cancellous bone volume when OE2 was stopped for either 4 or 8 days at a time. However, longer periods of OE2 omission did not affect bone volume, possibly because these were associated with an increase in bone resorption and/or a reduction in bone formation during the OE2-free period. In conclusion, we observed an increase in cancellous bone volume after prolonged treatment with oestrogen only if OE2 was omitted for short periods. This may be due, at least in part, to bone formation being maintained at a higher rate by such treatment than by either continuous OE2 administration or by intermittent administration where OE2 is discontinued for longer periods.
Journal of Endocrinology (1993) 139, 267–273
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We previously isolated a mammalian gene STC1 that encodes a glycoprotein related to stanniocalcin (STC), a fish hormone that plays a major role in calcium homeostasis. However, the mammalian STC1 gene is expressed in a variety of adult tissues in contrast to fish where STC is expressed only in one unique gland, the corpuscles of Stannius. This suggested that STC1 may have wider autocrine/paracrine functions in mammals. In the present study, using immunocytochemistry, we showed that STC1 protein is localized in the developing bone and muscle of the mouse fetus. During endochondral bone formation, STC1 is found principally in prechondrocytes and prehypertrophic chondrocytes. During intramembranous bone formation STC1 is present in the mesenchyme that is about to undergo ossification. STC1 is also found in the myocardiocytes of the developing heart and at all stages of differentiation from myoblasts to myotube formation in developing skeletal muscle. The specific localization of STC1 to chondrocytes and muscle cells suggests a role for this protein in chondrogenic and myogenic differentiation.
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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
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SUMMARY
Fifty-two mature female rats on a controlled diet were studied to compare the effects of oophorectomy, and hormone replacement therapy after oophorectomy, on femoral morphology and mineral content. Oophorectomy was followed by the development of osteoporosis after 11 months of observation. This was characterized by a reduction in ash per unit length of bone and a diminution of mid-shaft femoral cortical width. The administration of a progestogen (9 μg ethynodiol diacetate/rat/day) for 10 months after oophorectomy prevented the reduction in ash per unit length from occurring, whereas an oestrogen (0·9 μg mestranol/rat/day) had no significant effect on either parameter of osteoporosis. The progestogen appeared to produce this effect by a relative increase in periosteal new bone formation at the expense of increased loss of bone from the endosteal surface.
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Leptin is involved in regulating food intake, energy balance and bone formation. Increasing evidence suggests that leptin is also involved in fetal growth and development. The aim of this study was to determine if increased maternal leptin is followed by changes in body composition, skeletal growth or hormonal regulation in the adult rat offspring. Pregnant rats were given injections of either human recombinant leptin (3.5 mg/kg, i.p.) or vehicle on days 8, 10 and 12 of gestation. Both genders of leptin-exposed offspring showed significantly reduced adipose tIssue weight at adult age. Skeletal growth and cortical bone dimensions were significantly reduced. Circulating testosterone levels were significantly increased in female leptin-exposed offspring, and male leptin-exposed offspring had significant testicular enlargement. No significant effects were seen on circulating leptin levels or hypothalamic protein levels of the leptin receptor. The results demonstrate that maternally administered leptin is involved in fetal growth and development, leading to lean offspring with reduced skeletal growth.
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High levels of glucocorticoids are believed to alter bone remodeling by decreasing bone formation and increasing bone resorption. It has been suggested that different cytokines, like interleukin-6 (IL-6) and interleukin-1 (IL-1), are involved in bone resorption by activating immature osteoclasts, and some studies indicate that IL-6 promotes bone formation by a mitogenic effect on osteoblasts. The aim of the present investigation was to study whether cortisol regulates the expression of IL-6 and IL-1 beta in human osteoblast-like cells. A high dose of cortisol (10(-7)M) decreased, as expected, the C-terminal propeptide of type I collagen released into the culture medium. The IL-6 mRNA levels and IL-6 protein released into the culture medium were also decreased by cortisol in a dose-dependent manner. The maximum effect was seen at 1 microM cortisol (mRNA 23.1 +/- 7.9% of control culture; protein 28.2 +/- 8.3% of control culture). The decrease in IL-6 mRNA levels was apparent 4 h after the addition of cortisol and was still present 20 h later. The decrease in IL-6 protein released into the culture medium was seen 20 h later than the decrease in IL-6 mRNA levels. The production of IL-1 beta protein released into the culture medium was decreased in a dose-dependent manner after the addition of cortisol with a maximum effect at 1 microM. The effect of cortisol on IL-1 beta protein released into the culture medium was seen 16 h after the addition of cortisol. To summarize, cortisol decreases the expression of IL-6 as well as IL-1 beta in human osteoblast-like cells.
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Prostaglandin E2 (PGE2) has been shown to possess anabolic properties when administered systemically. All the experiments performed so far examined long bones from animals of varying age and bone status. In this study we compared the changes in bone mass of long bones (femur, tibia and humerus) to those in calvariae after a 3-week daily administration of 6 mg/kg PGE2 into 3-week-old rats. This regimen inhibited body weight gain (by 14.1%) as well as longitudinal growth of long bones (by 2.2-3.5%) but increased their mass. Ash weight (measuring both cancellous and compact bone) increased by 10.1-14.1% but tibial cancellous bone area was elevated by 54%. Radial growth was slightly reduced due to transient inhibition of mineral apposition rate at the periosteal envelope but the expansion of the marrow cavity was inhibited to a greater extent, resulting in an 8.1% increase in the relative compact bone area. The increased bone mass was associated with greater mechanical strength of the femoral neck (24.2% increase in fracture load and 19% in stiffness). In contrast, PGE2 administration did not affect calvarial thickness or mineral apposition rate but increased its density, i.e. reduced the area of marrow spaces due to stimulation of endocortical bone formation at this site. The pattern of bone mass changes documented in this study closely correlates with that of the induced expression of early-response genes following a single dose of PGE2 as we recently reported. These data, therefore, support the hypothesis that in vivo administration of an anabolic dose of PGE2 increases bone formation and augments bone mass largely by stimulating the recruitment of new osteoblasts via induction of the proliferation and/or differentiation of bone marrow osteogenic precursors.
