Stimulatory effects of estrogen and progesterone on proliferation and differentiation of normal human osteoblast-like cells in vitro

Scheven, Ben A.; Damen, Cora A.; Hamilton, Nicola J.; Verhaar, Harald J. J.; Duursma, S. A.

doi:10.1016/s0006-291x(05)80774-0

Cited by 106 publications

(54 citation statements)

References 20 publications

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“…Pertinent to this study, we found that progesterone (PG) stimulated human osteoblast cell proliferation (25,26) and increased IGFBP-5 mRNA levels (27). However, the molecular mechanism by which PG increased IGFBP-5 mRNA levels is not known.…”

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confidence: 79%

Progesterone Stimulation of Human Insulin-like Growth Factor-binding Protein-5 Gene Transcription in Human Osteoblasts Is Mediated by a CACCC Sequence in the Proximal Promoter

Boonyaratanakornkit

Strong

Mohan

et al. 1999

Journal of Biological Chemistry

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Insulin-like growth factor-binding protein-5 (IGFBP-5)is produced by osteoblasts and potentiates insulin-like growth factor mitogenic stimulation in osteoblast cell cultures. Progesterone (PG) increased IGFBP-5 expression in normal human osteoblasts and increased IGFBP-5 transcription in U2 human osteosarcoma cells. We developed a chloramphenicol acetyltransferase reporter construct containing the human IGFBP-5 proximal promoter sequence, which includes TATA and CAAT boxes, and five putative PG response element half-sites. 10 ؊8 M PG increased promoter activity of this construct in U2 cells co-transfected with a PG receptor isoform A (PR A ) expression vector. Analysis of 5 deletion constructs indicates that PG transactivation of IGFBP-5 promoter activity does not require the PG response element half-sites but does require the region ؊162 to ؊124 containing two tandem CACCC box sequences. Mutation of the proximal CACCC box at ؊139 eliminated PG transactivation. Gel shift assays using a ؊162 to ؊124 DNA fragment, U2 cell nuclear extracts, and purified PR A protein indicate that nuclear factors bind to a CACCC sequence at ؊139 and that PR A alters the pattern of transcription factor interaction with the CACCC sequence. Using a luciferase reporter construct containing base pairs ؊252 to ؉24 of the IGFBP-5 promoter, we found that both PR A and PR B isoforms mediated PG stimulation of promoter activity. These results suggest that PG may stimulate IGFBP-5 gene transcription via a novel mechanism involving PR and CACCC-binding factors.Insulin-like growth factor-binding protein-5 (IGFBP-5) 1 belongs to a family of six structurally related proteins that are unrelated to the IGF receptors and that bind IGF-I and IGF-II with high affinity (1-3). IGFBPs modulate the mitogenic and metabolic activities of the IGFs in vitro, suggesting an important role in IGF physiology in vivo. Of the various IGFBPs, IGFBP-5 is unique in that it stimulates IGF-induced osteoblastic cell proliferation when added simultaneously with IGF I or II to serumfree osteoblast-like cell cultures (4 -7). Recent evidence suggests that IGFBP-5 may stimulate cell proliferation by an IGF-independent mechanism involving IGFBP-5 specific cell surface binding sites (7,8). In addition, IGFBP-5 binds with high affinity to hydroxyapatite and to various extracellular matrix proteins, properties that are consistent with a role for this binding protein in fixing IGFs to extracellular matrices including mineralized bone (7, 9, 10). IGFBP-5 may be a more potent enhancer of IGF activities when bound to extracellular matrix than in solution (10). Coding sequences and 5Ј-flanking regions of IGFBP-5 genes are highly conserved in human, rat, and mouse (4, 5, 11-13), and the mouse and human 5Ј-flanking regions have been found to impart basal promoter activity to reporter gene constructs in several cell types, including osteoblasts (12-16).IGFBP-5 is expressed by a number of cell types including fibroblasts, myoblasts, and osteoblasts, and production of IG-FBP-5 is regulated ...

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confidence: 79%

Progesterone Stimulation of Human Insulin-like Growth Factor-binding Protein-5 Gene Transcription in Human Osteoblasts Is Mediated by a CACCC Sequence in the Proximal Promoter

Boonyaratanakornkit

Strong

Mohan

et al. 1999

Journal of Biological Chemistry

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“…(24,25) Some studies show that E 2 tends to be more of a differentiation-inducer, whereas P enhances osteoblast growth. (25,26) P appears also to inhibit bone resorption by mature osteoclasts isolated from rat long bones in a dose dependent manner (27) and pharmacological doses of progestagens decrease the urinary output of calcium and Hyp in humans. (28) Cyclic medroxyprogesterone increases spine BMD in women with abnormal menstrual cycles (29) and estrogen/progesterone replace- …”

Section: Discussionmentioning

confidence: 99%

Changes in Bone Resorption During the Menstrual Cycle

Chiu

Mayes³

et al. 1999

Journal of Bone and Mineral Research

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To determine if the cyclic changes of female sex hormones during the menstrual cycle are related to changes in bone formation and resorption, we measured serum bone-specific alkaline phosphatase (BAP) and osteocalcin (OC) and bone resorption markers, serum and urine deoxypyridinoline (Dpyr), three times per week during one menstrual cycle in 20 healthy premenopausal women. Serum estradiol (E 2 ) and progesterone (P) showed characteristic cyclic fluctuations. Serum Dpyr was higher during the follicular phase (

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“…Whether or not E 2 inhibits or enhances bone formation in vivo remains controversial (28). For instance, E 2 has been reported to increase (42), decrease (32,43), or have no effect (44,45) on various human osteoblast cell lines. In our fetal human osteoblasts (hFOB/ER), E 2 regulates gene expression and inhibits cell proliferation (34).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Regulation of a Transforming Growth Factor-β Inducible Early Gene That Inhibits Deoxyribonucleic Acid Synthesis in Human Osteoblasts*

et al. 1998

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This laboratory reported the identification and characterization of a unique three zinc finger, transcription factor-like, transforming growth factor-␤ inducible early gene (TIEG) (see Ref. 35). TIEG expression has been shown to be tissue-and cell type specific, enhanced by specific growth factors, and to decrease with advancing stages of breast cancer. Recent studies involving TIEG overexpression in pancreatic carcinoma cells indicate that TIEG expression inhibits DNA synthesis, similar to a tumor suppressor-like gene, and plays a role in apoptosis (see Ref. 37). This paper describes the rapid, but transient, induction of TIEG steady-state messenger RNA (mRNA) levels by 17␤-estradiol (E 2 ) in estrogen receptor (ER)-positive, human fetal osteoblastic (hFOB/ER) cells. This rapid induction is shown to be ERand steroid dose-dependent but protein synthesis independent. An antagonism between E 2 and PTH, which occurs in skeletal metabolism, is shown to concur rapidly with TIEG mRNA expression. Scanning confocal microscopy (using polarized, laser-based immunofluorescence) shows that TIEG protein is localized in the nucleus of hFOB/ER cells, with the levels rapidly increasing after E 2 treatment. The rapid E 2 -induced increase in TIEG expression is followed by an E 2 -induced inhibition of DNA synthesis in the hFOB/ER cells. Antiestrogens block not only the induction of TIEG mRNA levels but also the inhibition of cell proliferation. Lastly, hFOB cells, stably transfected with a TIEG expression vector, display markedly reduced DNA synthesis/cell proliferation, compared with nontransfected cells. These results support the finding that TIEG is an early responding regulatory gene for E 2 in human osteoblast cells that inhibits DNA synthesis. It is speculated that TIEG may play a role in the signaling pathway for E 2 in inhibiting cell proliferation. (Endocrinology 139: 1346 -1353, 1998) E STROGEN, an important regulator of bone metabolism, has been used clinically to prevent bone loss and reduce fracture risk in postmenopausal women (1-5). Studies both in vivo and in vitro in humans and animals have shown that 17␤-estradiol (E 2 ) decreases bone resorption and inhibits bone-resorbing osteoclast activities (4 -11). The effects of E 2 on bone-forming osteoblast functions, however, are less clear (1,(12)(13)(14)(15)(16)(17)(18). The discovery of estrogen receptors (ERs) in osteoblasts (19, 20) identified osteoblasts as potential target cells for E 2 . Other studies have reported that E 2 increases the production of cytokines and growth factors and their binding proteins by human osteoblasts, including interleukin-6 (21, 22), insulin-like growth factor-1 (IGF-1) (23-26), IGF binding proteins (27,28), and transforming growth factor-␤ (TGF-␤) (26,29). Indeed, one of the main results of E 2 action in osteoblasts is the induction of TGF-␤ production (5,26,29,30). TGF-␤, in turn, has major effects on osteoblasts, osteoclasts, and bone physiology, in general. It has been demonstrated that E 2 and PTH act as functional a...

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Stimulatory effects of estrogen and progesterone on proliferation and differentiation of normal human osteoblast-like cells in vitro

Cited by 106 publications

References 20 publications

Progesterone Stimulation of Human Insulin-like Growth Factor-binding Protein-5 Gene Transcription in Human Osteoblasts Is Mediated by a CACCC Sequence in the Proximal Promoter

Progesterone Stimulation of Human Insulin-like Growth Factor-binding Protein-5 Gene Transcription in Human Osteoblasts Is Mediated by a CACCC Sequence in the Proximal Promoter

Changes in Bone Resorption During the Menstrual Cycle

Estrogen Regulation of a Transforming Growth Factor-β Inducible Early Gene That Inhibits Deoxyribonucleic Acid Synthesis in Human Osteoblasts*

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