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Epidermal growth factor activates reproductive behavior independent of ovarian steroids in female rodents

MOLECULAR ENDOCRINOLOGY 2000年第7期14卷 1086-1098页

作者： Apostolakis, EM Gerai, J Lohmann, JE Clark, JH O'Malley, BW Baylor Coll Med Dept Cell Biol Houston TX 77030 USA Univ Pecs Sch Med Dept Pathophysiol Pecs Hungary

Sex steroids exert profound influence on neural development and function through activation of intranuclear receptors. However, during sexual differentiation and at onset of puberty, intracerebral estrogen (E) availability is subsequent to these effects. The potent mitogen epidermal growth factor (EGF) activates estrogen receptor (ER)-dependent transcription in cultured cells in the absence of exogenous E. Since reproductive behavior in female rodents is the result of E-dependent transcriptional activity and protein synthesis, lordosis serves as a well established in vivo model for probing cellular and molecular mechanisms of steroid receptor-dependent behavior. Here we demonstrate that EGF can signal through the classical E receptor (ER alpha) to alter in vivo function in rodent central nervous system. EGF and EGF receptor ligands induced lordosis in a dose- and time-dependent manner in the absence of steroid treatment in ovariectomized rats and mice. Using antisense oligonucleotides, pharmacological and antibody blockade, and mutant mice, we also report that this behavioral responsiveness is mediated through ER alpha by specific stimulation of membrane-bound EGF receptors and EGF receptor-specific tyrosine kinase rather than by direct ligand activation of the ER alpha. Of biological significance, delayed onset of puberty and the absence of synchronization between reproductive behavior and ovulation was detected in intact mutant Wa-2 mice that express a naturally occurring point mutation in the EGF receptor. To our surprise, EGF-mediated behavior was independent of progesterone (P) and progesterone receptor (PR) since antiprogestins, PR antisense oligonucleotides, and targeted disruption of PR in ovariectomized transgenic mice failed to impede the display of lordosis after EGF. Finally, we also found that another growth factor, insulinlike growth factor-1, which provokes ER-dependent transcription in vitro, activates mating behavior in a similar E-independent manne

关键词：脑/药物作用脑/代谢表皮生长因子/药理学雌激素受体α 胰岛素样生长因子ⅰ/药理学月经周期/药物作用月经周期/遗传学小鼠突变型小鼠转基因寡核苷酸类反义/药理学卵巢/代谢体位青春期/遗传学受体表皮生长因子/遗传学受体表皮生长因子/代谢受体雌激素/药物作用受体雌激素/代谢受体孕酮/遗传学受体孕酮/代谢生殖/药物作用性行为动物/药物作用甾类/生理学动物女(雌)性男(雄)性小鼠大鼠

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Salicylate-induced growth arrest is associated with inhibition of p70^s6k and down-regulation of c-Myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第49期275卷 38261-38267页

作者： Law, BK Waltner-Law, ME Entingh, AJ Chytil, A Aakre, ME Norgaard, P Moses, HL Vanderbilt Univ Vanderbilt Ingram Canc Ctr Nashville TN 37232 USA Vanderbilt Univ Dept Cell Biol Nashville TN 37232 USA Vanderbilt Univ Dept Mol Physiol & Biophys Nashville TN 37232 USA Glostrup Univ Hosp Inst Pathol Anat DK-2600 Glostrup Denmark

Salicylate and its pro-drug form aspirin are widely used medicinally for their analgesic and anti-inflammatory properties, and more recently for their ability to protect against colon cancer and cardiovascular disease, Despite the wide use of salicylate, the mechanisms underlying its biological activities are largely unknown. Recent reports suggest that salicylate may produce some of its effects by modulating the activities of protein kinases. Since we have previously shown that the farnesyltransferase inhibitor L-744,832 inhibits cell proliferation and p70(s6k) activity, and salicylate inhibits cell proliferation, we examined whether salicylate affects p70(s6k) activity. We find that salicylate potently inhibits p70(s6k) activation and phosphorylation in a p38 MAPK-independent manner. Interestingly, low salicylate concentrations (less than or equal to 250 muM) inhibit p70(s6k) activation by phorbol myristate acetate, while higher salicylate concentrations (greater than or equal to5 mM) are required to block p70(s6k) activation by epidermal growth factor + insulin-like growth factor-1, These data suggest that salicylate may selectively inhibit p70(s6k) activation in response to specific stimuli. Inhibition of p70(s6k) by salicylate occurs within 5 min, is independent of the phosphatidylinositol 3-kinase pathway, and is associated with dephosphorylation of p70(s6k) on its major rapamycin-sensitive site, Thr(389). A rapamycin-resistant mutant of p70(s6k) is resistant to salicylate-induced Thr(389) dephosphorylation.

关键词：醋氨酚/药理学镇痛药/药理学消炎药非甾类/药理学阿司匹林/药理学细胞分裂/药物作用细胞分裂/生理学细胞系细胞周期蛋白A/遗传学细胞周期蛋白D1/遗传学表皮生长因子/药理学基因表达调控/药物作用基因 myc 吲哚美辛/药理学胰岛素样生长因子ⅰ/药理学丝裂原激活蛋白激酶类/代谢增殖细胞核抗原/遗传学原癌基因蛋白质c-myc/遗传学核糖体蛋白质S6激酶类/拮抗剂和抑制剂水杨酸盐类/药理学十四酰佛波乙酯/药理学 p38丝裂原活化蛋白激酶类动物人类小鼠

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Expression and release of insulin-like growth factor binding proteins in isolated epiphyseal growth plate chondrocytes from the ovine fetus

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第2期183卷 172-181页

作者： De los Rios, P Hill, DJ Univ Western Ontario St Josephs Hlth Ctr Lawson Res Inst London ON N6A 4V2 Canada Univ Western Ontario Dept Physiol London ON Canada Univ Western Ontario Dept Med London ON Canada Univ Western Ontario Dept Paediat London ON Canada

Insulin-like growth factor-ii (IGF-II) is an autocrine modulator of epiphyseal chondrogenesis in the fetus. The cellular availability of ICFs are influenced by the IGF-binding proteins (ICFBPs). In this study, we investigated the control of expression and release of ICFBPs from isolated epiphyseal growth plate chondrocytes from the ovine fetus by hormones and growth factors implicated in the chondrogenic process. Chondrocytes were isolated from the proliferative zone of the fetal ovine proximal tibial growth plate and maintained in monolayer culture at early passage number. Culture media conditioned by chondrocytes under basal conditions released ICFBPs of 24, 34, and 29 kDa, and a less abundant species of 39-43 kDa that were identified immunologically as IGFBP-4, IGFBP-2, IGFBP-5, and IGFBP-3, respectively. Messenger RNAs encoding each species were identified by Northern blot analysis within chondrocytes, as was mRNA encoding IGFBP-6. Exposure to ICF-I or IGF-II (13 or 26 nM) caused an increase in expression and release of 1GFBP-3. The release of 1GFBP-2 and IGFBP-5 were also potentiated without changes to steady state mRNA, and for IGFBP-5 this was due in part to a release from the cell membrane in the presence of ICF-II. Insulin (16.7 or 167 nM)selectively increased mRNA and the release of IGFBP-3, while cortisol il or 5 mu M) inhibited both mRNA and release of IGFBP-2 and ICFBP-5, Transforming growth factor-beta 1 (TGF-beta 1) (0.1 or 0.2 nM) increased the expression and release of IGFBP-3. and caused an increase in mRNAs encoding IGFBP-2 and ICFBP-5. Neither growth hormone (GH), Fibroblast growth factor-2, nor thyroxine (T-4) had any effect on IGFBP expression or release. The results suggest that IGFBP expression and release within the developing growth plate can be modulates by IGF-II and other trophic factors, thus controlling IGF availability and action. (C) 2000 Wiley-Liss, Inc.

关键词：细胞培养的软骨细胞/药物作用软骨细胞/代谢软骨细胞/分泌软骨发生/遗传学软骨发生/生理学胎儿/细胞学胎儿/代谢基因表达调控发育期/药物作用生长面/细胞学生长面/代谢生长面/分泌氢化可的松/药理学胰岛素/药理学胰岛素样生长因子结合蛋白质类/遗传学胰岛素样生长因子结合蛋白质类/分泌胰岛素样生长因子ⅰ/药理学胰岛素样生长因子Ⅱ/药理学 RNA 信使/遗传学 RNA 信使/代谢绵羊转化生长因子β/药理学动物

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Effects of recombinant human insulin-like growth factor I administration on spontaneous and growth hormone (GH)-releasing hormone-stimulated GH secretion in anorexia nervosa

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JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2000年第8期85卷 2805-2809页

作者： Gianotti, L Pincelli, AI Scacchi, M Rolla, M Bellitti, D Arvat, E Lanfrano, F Torsello, A Ghigo, E Cavagnini, F Müller, EE Univ Milan Dept Pharmacol I-20129 Milan Italy Univ Pisa Univ Adolescentol I-56100 Pisa Italy Univ Milan San Luca Hosp Chair Endocrinol 2 I-20149 Milan Italy Univ Turin Dept Internal Med Div Endocrinol I-10126 Turin Italy

Exaggerated GH and reduced insulin-like growth factor I (IGF-I) level are common features in anorexia nervosa (AN). A reduction of the negative IGF-I feedback could account, in part, for GH hypersecretion. To ascertain this, we studied the effects of recombinant human (rh)IGF-I on spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in nine women with AN [body mass index, 14.1 +/- 0.6 kg/m(2)] and in weight matched controls (normal weight). Mean basal GH concentrations (mGHc) and GHRH (2.0 mug/kg, iv) stimulation were significantly higher in AN. rhIGF-I administration (20 mug/kg, sc) significantly reduced mGHc in AN (P < 0.01), but not normal weight, and inhibited peak GH response to GHRH in both groups;mGHc and peak GH, however, persisted at a significantly higher level in AN. Insulin, glucose, and IGFBP-1 basal levels were similar in both groups. rhIGF-I inhibited insulin in AN, whereas glucose remained unaffected in both groups. IGFBP-1 increased in both groups (P < 0.05), with significantly higher levels in AN. IGFBP-3 was under basal conditions at a lower level in AN (P < 0.05) and remained unaffected by rhIGF-I. This study demonstrates that a low rhIGF-I dose inhibits, but does not normalize, spontaneous and GHRH-stimulated GH secretion in AN, pointing also to the existence of a defective hypothalamic control of GH release. Moreover, the increased IGFBP-1 levels might curtail the negative IGF-I feedback in AN.

关键词：神经性厌食/血液神经性厌食/病理生理学血糖/代谢雌二醇/血液反馈卵泡刺激素/血液生长激素释放激素/投药和剂量生长激素释放激素/药理学人生长激素/血液人生长激素/代谢注射皮下胰岛素/血液胰岛素/代谢胰岛素样生长因子结合蛋白质1/血液胰岛素样生长因子Ⅰ/投药和剂量胰岛素样生长因子Ⅰ/代谢胰岛素样生长因子ⅰ/药理学促黄体激素/血液重组蛋白质类/投药和剂量重组蛋白质类/药理学参考值青少年成年人女(雌)性人类

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Synergistic effects of insulin-like growth factor-I and human chorionic gonadotropin in the rat ovary

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METABOLISM-CLINICAL AND EXPERIMENTAL 2000年第3期49卷 314-320页

作者： Damario, MA Bogovich, K Liu, HC Rosenwaks, Z Poretsky, L Cornell Univ Med Ctr New York Hosp Dept Obstet & Gynecol New York NY 10021 USA Cornell Univ Med Ctr New York Hosp Dept Med New York NY 10021 USA Univ S Carolina Sch Med Dept Obstet & Gynecol Columbia SC USA

Insulin and low doses of luteinizing hormone (LH) activity (human chorionic gonadotropin [hCG]) act synergistically in the rat to produce anovulation, large ovarian cysts, and elevated plasma androstenedione levels. Further, both insulin and insulin-like growth factor-1 (IGF-I) affect the ability of gonadotropins to enhance both ovarian theca and granulosa cell function in vitro. The present series of experiments were performed to determine if recombinant human IGF-I (rhIGF-1) can act in a manner similar to insulin when combined with subovulatory doses of hCG in adult normally cycling rats. Fifty-four female Sprague-Dawley rats were randomly assigned to the following treatment groups at the age of 64 days: (A) vehicle alone (controls, phosphate-buffered saline containing 0.09% pig gelatin), (B) twice-daily subcutaneous injections of 0.5 to 3.0 U insulin, (C) twice-daily subcutaneous injections of 1.5 U hCG, to both insulin and hCG, (E) twice-daily subcutaneous injections of rhIGF-1 (2.5 mg/kg/d), and (F) both hCG and rhIGF-1. After 22 days of treatment, the animals were killed on day 23, trunk blood was collected, and the ovaries were excised for histological study. Eight of 9 control rats and 5 or 6 of 9 rats treated with insulin, hCG, or rhIGF-1 alone displayed normal estrus cycles throughout the in vivo treatment period as assessed by daily vaginal smears. In marked contrast, only 1 animal treated with hCG + insulin and 2 animals treated with hCG + rhIGF-1 continued to display vaginal smears indicative of normal cycling. Multiple large ovarian follicular cysts were found only in these latter 2 groups (3 of 9 animals in each group). Mean serum testosterone levels were significantly elevated in animals receiving insulin + hCG (0.72 +/- 0.28 v 0.17 +/- 0.03 ng/mL in controls, P = .05). Mean serum androstenedione levels were significantly elevated in animals receiving hCG and animals receiving rhIGF-1 + hCG (5.57 +/- 0.99 and 2.39 +/- 0.68 ng/mL, respectively, v 0.14

关键词：雄烯二酮/血液绒毛膜促性腺激素/血液绒毛膜促性腺激素/药理学药物协同作用雌二醇/血液动情期/药物作用动情期/生理学胰岛素/血液胰岛素/药理学胰岛素样生长因子Ⅰ/药代动力学胰岛素样生长因子ⅰ/药理学卵巢囊肿/化学诱导卵巢囊肿/病理学卵巢/细胞学卵巢/药物作用卵巢/生理学大鼠 Sprague-Dawley 重组蛋白质类/血液重组蛋白质类/药理学睾酮/血液动物女(雌)性人类大鼠

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Proliferation of mouse mammary epithelial cells in vitro:: Interactions among epidermal growth factor, insulin-like growth factor I, ovarian hormones, and extracellular matrix proteins

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ENDOCRINOLOGY 2000年第10期141卷 3578-3586页

作者： Woodward, TL Xie, JW Fendrick, JL Haslam, SZ Michigan State Univ Dept Physiol E Lansing MI 48824 USA

The purpose of the present study was to investigate the role of extracellular matrix proteins (ECMs;collagens I and IV, fibronectin, and laminin) in modulating proliferative responses of normal mammary epithelial cells in serum-free culture to epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I). As EGF and IGF-I can alter steroid responses, the interactions among growth factors, estrogen, and R5020 were also investigated. We report the novel finding that all ECMs tested, but not a nonspecific attachment factor, poly-L-lysine (PL), promoted a highly synergistic proliferative response to EGF plus IGF-I. EGF receptors were significantly increased with culture time on all ECMs, but not on FL. IGF receptor expression was significantly 2- to 4-fold higher on all ECMs compared with FL. EGF decreased IGF-binding protein-2 (IGFBP-2) and IGFBP-3 by more than 50% in the presence of IGF-I on PL or collagen I. These results indicate that ECM-specific IGF-I/EGF synergism occurs in response to ECM up-regulation of growth factor receptors and EGF down-regulation of inhibitory IGFBPs. Growth factors did not synergize with estrogen and/or R5020. Instead, estrogen plus R5020 decreased EGF-plus IGF-I-induced proliferation in an ECM-dependent manner. These studies demonstrate that proliferation of normal mammary epithelial cells involves complex interactions among steroids, growth factors, binding proteins, and ECMs.

关键词：细胞分裂/药物作用细胞培养的药物协同作用表皮生长因子/药理学上皮细胞/细胞学上皮细胞/代谢细胞外基质/代谢细胞外基质蛋白质类/药理学激素类/代谢激素类/药理学胰岛素样生长因子结合蛋白质类/代谢胰岛素样生长因子ⅰ/药理学乳腺动物/细胞学乳腺动物/代谢卵巢/代谢受体雌激素/代谢受体孕酮/代谢动物女(雌)性小鼠

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Stat 5B, activated by insulin in a Jak-independent fashion, plays a role in Glucokinase gene transcription

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ENDOCRINOLOGY 2000年第6期141卷 1977-1988页

作者： Sawka-Verhelle, D Tartare-Deckert, S Decaux, JF Girard, J Van Obberghen, E INSERM U145 Fac Med F-06107 Nice 2 France CNRS UPR 1524 F-92190 Meudon France

Stat proteins are SH2 domain-containing transcription factors that are activated by various cytokines and growth factors. In a previous work, we have identified Stat 5B as a substrate of the insulin receptor based on yeast two-hybrid and mammalian cell transfection studies. In the present study, we have approached the biological relevance of the interaction between the insulin receptor and the transcription factor Stat 5B. Firstly, we show that both insulin and insulin-like growth factor I lead to tyrosine phosphorylation of Stat 5B, and this promotes binding of the transcription factor to the beta-casein promoter containing a Stat 5 binding site. Further, we demonstrate that insulin stimulates the transcriptional activity of Stat 5B. Activation of Stat 5B by insulin appears to be Jak2-independent, whereas Jak2 is required for GH-induced Stat: 5B activation. Hence the pathway by which Stat 5B is activated by insulin is different from that used by GH. In addition, by using Jak1- and Tyk2-deficient cells we exclude the involvement of both Jak1 and Tyk2 in Stat 5B activation by insulin. Taken together, our results strengthen the notion that insulin receptor can directly activate Stat 5B. More importantly, we have identified a Stat 5 binding site in the human hepatic glucokinase promoter, and we show that insulin leads to a Stat 5B-dependent increase in transcription of a reporter gene carrying this promoter. These observations favor the idea that Stat 5B plays a role in mediating the expression of the glucokinase gene induced by insulin. As a whole, our results provide evidence for the occurrence of a newly identified circuit in insulin signaling in which the cell surface receptor is directly linked to nuclear events through a transcription factor. Further, we have revealed an insulin target gene whose expression is, at least in part, dependent on Stat 5B activation and/or binding.

关键词： 3T3细胞癌肝细胞/代谢 DNA/代谢 DNA结合蛋白质类/生理学葡糖激酶/遗传学胰岛素/药理学胰岛素样生长因子ⅰ/药理学 Janus激酶1 Janus激酶2 肝/酶学肝肿瘤/代谢乳蛋白质类诱变定点磷酸酪氨酸/代谢蛋白酪氨酸激酶类/生理学原癌基因蛋白质类 STAT5转录因子反式激活因子类/生理学转录遗传转染肿瘤细胞培养的动物人类小鼠

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Insulin-like growth factor binding protein-3 is regulated by dihydrotestosterone and stimulates deoxyribonucleic acid synthesis and cell proliferation in LNCaP prostate carcinoma cells

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ENDOCRINOLOGY 2000年第7期141卷 2401-2409页

作者： Martin, JL Pattison, SL Univ Sydney Royal N Shore Hosp Kolling Inst Med Res St Leonards NSW 2065 Australia

We have investigated the production and actions of a growth regulatory protein, insulin-like growth factor binding protein (TGFBP)-3, in the androgen-responsive prostate carcinoma cell line LNCaP. Confluent monolayers of cells secreted approximately 0.7 ng/ml IGFBP-3 over 24 h. Dihydrotestosterone (DHT, 10 nM) and 1,25-dihydroxyvitamin D-3 (vitamin D, 10 nM) increased IGFBP-3 in media to 149 +/- 15% and 206 +/- 18% of control, respectively, when added separately, and to 453 +/- 28% of control when used in combination. IGFBP-2, secreted at approximately 25-fold higher concentrations than IGFBP-3, was increased 50% by 10 nM DHT, but there was no effect of vitamin D on IGFBP-2 production in the absence or presence of DHT. Cell-associated IGFBP-3, and immunoreactive IGFBP-3 species of 20 kDa and 30 kDa were also increased in response to vitamin D plus DHT. A combination of vitamin D and DHT increased DNA synthesis in LNCaP cells 3-fold, and this was at least partly mediated by endogenous IGFBP-3 because anti-IGFBP-3 IgG, but not nonimmune serum IgG, reduced the stimulatory effect of vitamin D and DHT from 293 +/- 11.6% to 161 +/- 30.7% of control levels (P < 0.0001). Basal and DHT plus vitamin D-stimulated thymidine incorporation was significantly increased by 50 ng/ml human plasma-derived purified IGFBP-3. After 4 days treatment with vitamin D plus DHT, or pure IGFBP-3, LNCaP cell numbers were increased relative to control. These results indicate a role for IGFBP-3 in the proliferation of androgen-responsive prostate carcinoma cells.

关键词：胰岛素样生长因子ⅰ/药理学前列腺肿瘤/代谢前列腺肿瘤/病理学胸苷/代谢肿瘤细胞培养的维生素D/药理学男(雄)性

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Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation

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ENDOCRINOLOGY 2000年第5期141卷 1667-1674页

作者： Deckers, MML Karperien, M van der Bent, C Yamashita, T Papapoulos, SE Löwik, CWGM Leiden Univ Med Ctr Dept Endocrinol & Metab Dis NL-2333 ZA Leiden Netherlands Leiden Univ Med Ctr Dept Pediat NL-2333 ZA Leiden Netherlands Kirin Brewery Co Ltd Pharmaceut Res Lab Takasaki Gumma 37012 Japan

Endochondral bone formation is regulated by systemically and locally acting growth factors. A role for vascular endothelial growth factor (VEGF) in this process has recently been proposed, because inactivation of VEGF inhibits endochondral bone formation via inhibition of angiogenesis. Despite the known effect of VEGF as specific endothelial growth factor, its effects on osteoblast differentiation have not been studied. Ee, therefore, examined the expression of VEGF-A, -B, -C, and -D and their receptors in a model of osteoblast differentiation using the mouse preosteoblast-like cell line KS483. Early in differentiation, KS483 cells express low levels VEGF-A, -B, and -D messenger RNA, whereas during mineralization, R5483 cells express high levels. In addition, expression of the VEGF receptors, VEGFR1, VEGFR2, and VEGF165R/neuropilin, coincided with expression of their ligands, being maximally expressed during mineralization. VEGF-A production during osteoblast differentiation was stimulated by insulin-like growth factor I that enhances osteoblast differentiation and was inhibited by PTH-related peptide that inhibits osteoblast differentiation. Furthermore, continuous treatment of KS483 cells with recombinant human VEGF-A stimulated nodule formation. Although treatment of KS483 cells with soluble FLT1, an agent that blocks binding of VEGF-A and -B to VEGFR1, did not inhibit nodule formation, this observation does not exclude involvement of VEGFR2 in the regulation of osteoblast differentiation. As it is known that VEGF-A, -C, and -D can act through activation of VEGFR2, other isoforms might compensate for VEGF-A loss. The expression pattern of VEGFs and their receptors shown here suggests that VEGFs play an important role in the regulation of bone remodeling by attracting endothelial cells and osteoclasts and by stimulating osteoblast differentiation.

关键词：细胞分化细胞系电泳聚丙烯酰氨凝胶内皮生长因子/生物合成内皮生长因子/遗传学酶联免疫吸附测定胰岛素样生长因子ⅰ/药理学淋巴因子/生物合成成骨细胞/生理学甲状旁腺激素相关蛋白质聚合酶链反应蛋白质类/药理学 RNA 信使/代谢受体蛋白质酪氨酸激酶类/生物合成受体细胞表面/生物合成受体生长因子/生物合成受体血管内皮生长因子血管内皮生长因子A 血管内皮生长因子B 血管内皮生长因子C 血管内皮生长因子D 血管内皮生长因子受体3 血管内皮生长因子类动物人类小鼠

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Dietary protein restriction lowers plasma insulin-like growth factor I (IGF-I), impairs cortical bone formation, and induces osteoblastic resistance to IGF-I in adult female rats

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ENDOCRINOLOGY 2000年第9期141卷 3149-3155页

作者： Bourrin, S Ammann, P Bonjour, JP Rizzoli, R Univ Hosp Geneva Dept Internal Med Div Bone Dis WHO Collaborating Ctr Osteoporosis & Bone Dis CH-1211 Geneva 14 Switzerland

Dietary protein deficiency, common in elderly, is associated with decreased areal bone mineral density and plasma insulin-like growth factor I (IGF-I). To investigate the early adaptation of bone cells to protein restriction, B-month-old female rats were pair-fed with isocaloric 15% (control) or 2.5% casein diets for 14 days. Animals were then treated daily with rhIGF-I/IGFBP-3 (1:4, 2.5 mg IGF-I/kg BW) or with vehicle for 10 days. After double-labeling, proximal metaphysis and mid-diaphysis of the tibia were analyzed histomorphometrically. Plasma ostcocalcin, IGF-I, and urinary deoxypyridinoline were quantified. After 14 days of protein restriction, significant drops in plasma osteocalcin (13%) and IGF-I (37%), in periosteal formation (83%) and mineral apposition (49%) rates are observed, indicating a decreased osteoblast recruitment and activity. In cancellous bone, a significant decrease in active eroded surfaces (27%) and osteoclast number (24%) indicates a transient depression of resorption. In rats fed the 15% casein diet, rhIGF-I/IGFBP-3 increases cancellous (42%) and periosteal (600%) formation rates, indicating an increased osteoblast recruitment. In protein-restricted rats, rhIGF-I/IGFBP-3 fails to increase cancellous or periosteal bone formation and plasma osteocalcin is significantly lower than in 15% casein+rhIGF-I/IGFBP-3 rats. Protein restriction induces osteoblast resistance to rhIGF-I/IGFBP-3 in both bone envelopes. Low plasma IGF-I and osteoblast resistance to IGF-I, may contribute to the impaired periosteal formation.

关键词：生物学标记体重/药物作用骨发育/生理学骨质吸收/病理学骨和骨组织/细胞学膳食膳食蛋白质类/投药和剂量抗药性胰岛素样生长因子结合蛋白质3/药理学胰岛素样生长因子Ⅰ/代谢胰岛素样生长因子ⅰ/药理学器官测量/药物作用成骨细胞/药物作用大鼠 Sprague-Dawley 重组蛋白质类/药理学动物女(雌)性大鼠

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