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ANDROGENS SUPPRESS OSTEOCLAST FORMATION INDUCED BY RANK LIGAND AND M-CSF

Huber, Dustin Michael
http://rave.ohiolink.edu/etdc/view?acc_num=ucin999020063

Abstract Details

2001, PhD, University of Cincinnati, Medicine : Molecular, Cellular and Biochemical Pharmacology.
Osteoporosis leads to fracture and a simultaneous increase in mortality from such injuries. Individuals over the age of 50 are especially prone to osteoporosis, in part due to their age and the resulting deficit in sex steroid hormones. Androgen deficiency in males leads to an increase in osteoclastic bone resorption and a progressive decrease in bone mineral density. Demineralization in key structural regions of bone reduces skeletal integrity and increases the risk of fracture, analogous to that observed in females following menopause. Therefore, androgens may play a similar role to estrogens in the direct regulation of the bone resorbing cell, the osteoclast. Steroid control over osteoclast differentiation and proliferation may help prevent the onset of age-related osteoporosis. We examined the ability of testosterone (T) and 5α-dihydrotestosterone (5α-DHT) to suppress osteoclast formation induced by receptor activator NF-κB (RANK) ligand and macrophage colony stimulating factor (M-CSF) in vitro. Androgens suppressed the osteoclast formation from bone marrow monocytes (BMMs) of both normal and orchidectomized mice. Interestingly, 17β-estradiol was as effective as both T and 5α-DHT in suppressing osteoclast formation in BMMs from both normal and orchidectomized mice. A similar sensitivity to both sex hormones was observed following ovariectomy. As with BMMs, T and 5α-DHT also suppressed osteoclast formation in RAW264.7 cells indicating that the suppressive effects of androgens on osteoclastogenesis are direct and do not require stromal cells. In RAW264.7 cells, androgens inhibit RANKL-induced osteoclast formation through selective regulation of c-Jun. Increases in precursor number following orchidectomy led us to also examine the ability of the sex steroids to inhibit proliferation of these cells. Both androgens and estrogens appear to inhibit M-CSF- mediated proliferation of both BMM and RAW264.7 cells. The proliferative effect was due in part to upregulation of cyclin D1 levels in the bone marrow monocytes and early precursor cells. These studies indicate that sex steroids suppress osteoclast formation via a direct action on osteoclast precursors to block key transcription factors such as c-Jun essential for osteoclast differentiation, and to inhibit the numbers of new osteoclast precursor cells that are produced in the bone marrow.
J. Pike (Advisor)
ANDROGENS; OSTEOCLAST; RANK; M-CSF; PROLIFERATION

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Citations

  • Huber, D. M. (2001). ANDROGENS SUPPRESS OSTEOCLAST FORMATION INDUCED BY RANK LIGAND AND M-CSF [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin999020063

    APA Style (7th edition)

  • Huber, Dustin. ANDROGENS SUPPRESS OSTEOCLAST FORMATION INDUCED BY RANK LIGAND AND M-CSF. 2001. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin999020063.

    MLA Style (8th edition)

  • Huber, Dustin. "ANDROGENS SUPPRESS OSTEOCLAST FORMATION INDUCED BY RANK LIGAND AND M-CSF." Doctoral dissertation, University of Cincinnati, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin999020063

    Chicago Manual of Style (17th edition)

ucin999020063
© 2001, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.