Kevin G. Osteen, Ph.D.
Director Division of Women's Reproductive Health and Research Center
Professor of Obstetrics and Gynecology
Professor of Pathology
Vanderbilt University Medical Center
Nashville, TN 37232-2519
Cellular and molecular mechanisms controlling growth and differentiation in the female reproductive tract
Among normal adult tissues, the endometrial lining of the human uterus undergoes perhaps the most dynamic cycle of steroid controlled growth, differentiation and tissue breakdown. The rate of estrogen-driven cell growth during the proliferative phase of the menstrual cycle rivals that of many tumors while progesterone inhibits endometrial growth and appears to provide protection from the development of both benign diseases and certain neoplasms. Ovarian steroids clearly control the endometrium and endometrial activity; however, steroids alone cannot account for the entire orchestration of such well-controlled and often focal patterns of cellular proliferation and differentiation which are observed. To better understand steroid sensitive tissue behavior, my research laboratory has focused on the endometrium as a model to identify interrelationships between steroid action and stromal-epithelial cell communication via specific paracrine factors. Of special interest to us are the cellular and molecular mechanisms which control steroid-dependent versus steroid-independent expressions of metalloproteinases. These enzymes are necessary for degradation of extracellular matrix proteins and play important roles in the extensive tissue remodeling which normally occurs during the menstrual cycle as well as during establishment of the hemochorial placenta. Metalloproteinases may also contribute to the pathophysiology of endometrial dysfunction including abnormal bleeding, defects of placentation and the extrauterine disease endometriosis. Recently, we have extended our studies to investigate altered metalloproteinase gene and protein expression relative to the reproductive toxicology of dioxin.
- Taylor, HS, Osteen, KG, Bruner-Tran, KL, Krikun, G, Sokalska, A, Duleba, AJ Novel Therapies Targeting Endometriosis. Reprod Sci, 2011.
- McConaha, ME, Ding, T, Lucas, JA, Arosh, JA, Osteen, KG, Bruner-Tran, KL Preconception omega-3 fatty acid supplementation of adult male mice with a history of developmental TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) exposure prevents preterm birth in unexposed female partners. Reproduction, 2011.
- Herington, JL, Crispens, MA, Carvalho-Macedo, AC, Camargos, AF, Lebovic, DI, Bruner-Tran, KL, Osteen, KG Development and prevention of postsurgical adhesions in a chimeric mouse model of experimental endometriosis. Fertil Steril, 2010.
- Ding, T, McConaha, M, Boyd, KL, Osteen, KG, Bruner-Tran, KL Developmental dioxin exposure of either parent is associated with an increased risk of preterm birth in adult mice. Reprod Toxicol, 2010.
- Bruner-Tran, KL, Osteen, KG Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reprod Toxicol, 2010.
- Bruner-Tran, KL, Ding, T, Osteen, KG Dioxin and endometrial progesterone resistance. Semin Reprod Med, 28(1), 59-68, 2010.
- Bruner-Tran, KL, Osteen, KG Dioxin-like PCBs and endometriosis. Syst Biol Reprod Med, 56(2), 132-46, 2010.
- Bruner-Tran, KL, Carvalho-Macedo, AC, Duleba, AJ, Crispens, MA, Osteen, KG Experimental endometriosis in immunocompromised mice after adoptive transfer of human leukocytes. Fertil Steril, 93(8), 2519-24, 2010.
- Bruner-Tran, K, Osteen, KG, Taylor, HS, Sokalska, A, Haines, K, Duleba, AJ Resveratrol Inhibits Development of Experimental Endometriosis In Vivo and Reduces Endometrial Stromal Cell Invasiveness In Vitro. Biol Reprod, 2010.
- Krikun, G, Hu, Z, Osteen, K, Bruner-Tran, KL, Schatz, F, Taylor, HS, Toti, P, Arcuri, F, Konigsberg, W, Garen, A, Booth, CJ, Lockwood, CJ The immunoconjugate "icon" targets aberrantly expressed endothelial tissue factor causing regression of endometriosis. Am J Pathol, 176(2), 1050-6, 2010.
- Bruner-Tran, KL, Osteen, KG, Duleba, AJ Simvastatin protects against the development of endometriosis in a nude mouse model. J Clin Endocrinol Metab, 94(7), 2489-94, 2009.
- Bruner-Tran, KL, Yeaman, GR, Crispens, MA, Igarashi, TM, Osteen, KG Dioxin may promote inflammation-related development of endometriosis. Fertil Steril, 89(5 Suppl), 1287-98, 2008.
- Nayyar, T, Bruner-Tran, KL, Piestrzeniewicz-Ulanska, D, Osteen, KG Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis. Reprod Toxicol, 23(3), 326-36, 2006.
- Bruner-Tran, KL, Zhang, Z, Eisenberg, E, Winneker, RC, Osteen, KG Down-regulation of Endometrial MMP-3 and MMP-7 Expression in vitro and Therapeutic Regression of Experimental Endometriosis in vivo by a Novel Nonsteroidal Progesterone Receptor Agonist, Tanaproget. J Clin Endocrinol Metab, 91(4), 1554-60, 2006.
- Harris, HA, Bruner-Tran, KL, Zhang, X, Osteen, KG, Lyttle, CR A selective estrogen receptor-beta agonist causes lesion regression in an experimentally induced model of endometriosis. Hum Reprod, 20(4), 936-41, 2005.
- Osteen, KG, Bruner-Tran, KL, Eisenberg, E Endometrial biology and the etiology of endometriosis. Fertil Steril, 84(1), 33-4; discussion 38-9, 2005.
- Igarashi, TM, Bruner-Tran, KL, Yeaman, GR, Lessey, BA, Edwards, DP, Eisenberg, E, Osteen, KG Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fertil Steril, 84(1), 67-74, 2005.
- Osteen, KG, Bruner-Tran, KL, Eisenberg, E Reduced progesterone action during endometrial maturation: a potential risk factor for the development of endometriosis. Fertil Steril, 83(3), 529-37, 2005.
- Kurita, T, Medina, R, Schabel, AB, Young, P, Gama, P, Parekh, TV, Brody, J, Cunha, GR, Osteen, KG, Bruner-Tran, KL, Gold, LI The activation function-1 domain of estrogen receptor alpha in uterine stromal cells is required for mouse but not human uterine epithelial response to estrogen. Differentiation, 73(6), 313-22, 2005.
- Osteen, KG, Igarashi, TM, Yeaman, GR, Bruner-Tran, KL Steroid and cytokine regulation of matrix metalloproteinases and the pathophysiology of endometriosis. Gynecol Obstet Invest, 57(1), 53-4, 2004.
- Fortin M, Lépine M, Pagé M, Osteen K, Massie B, Hugo P, Steff A-M "An improved mouse model for endometriosis allows noninvasive assessment of lesion implantation and development." Fertil and Steril, 80,Suppl 2832-838, 2003.
- Fortin, M, LÃ©pine, M, PagÃ©, M, Osteen, K, Massie, B, Hugo, P, Steff, AM An improved mouse model for endometriosis allows noninvasive assessment of lesion implantation and development. Fertil Steril, 80 Suppl 2832-8, 2003.
- Hull ML, Charnock-Jones DS, Chan CL, Bruner-Tran KL, Osteen KG, Tom BD, Fan TP, Smith SK "Antiangiogenic agents are effective inhibitors of endometriosis." J Clin Endocrinol Metab, 882889-2899, 2003.
- Hull, ML, Charnock-Jones, DS, Chan, CL, Bruner-Tran, KL, Osteen, KG, Tom, BD, Fan, TP, Smith, SK Antiangiogenic agents are effective inhibitors of endometriosis. J Clin Endocrinol Metab, 88(6), 2889-99, 2003.
- Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA, Giudice, LC "Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility." Endocrinology, 1442870-2881, 2003.
- Osteen, Kevin G, Yeaman, Grant R, Bruner-Tran, Kaylon L Matrix metalloproteinases and endometriosis. Semin Reprod Med, 21(2), 155-64, 2003.
- Osteen, Kevin G, Igarashi, Toshio M, Bruner-Tran, Kaylon L Progesterone action in the human endometrium: induction of a unique tissue environment which limits matrix metalloproteinase (MMP) expression. Front Biosci, 8d78-86, 2003.
- Apparao, KB, Illera MJ, Beyler SA, Olson GE, Osteen KG, Corjay MH, Boggess K, Lessey, BA "Regulated expression of osteopontin in the peri-implantation rabbit uterus." Biol Reprod, 681484-1490, 2003.
- Curry, TE, Osteen, KG The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev, 24(4), 428-65, 2003.
- Bruner-Tran, KL, Webster-Clair, D, Osteen, KG Experimental endometriosis: the nude mouse as a xenographic host. Ann N Y Acad Sci, 955328-39; discussion 340-2, 396-406, 2002.
- Osteen, KG, Bruner-Tran, KL, Ong, D, Eisenberg, E Paracrine mediators of endometrial matrix metalloproteinase expression: potential targets for progestin-based treatment of endometriosis. Ann N Y Acad Sci, 955139-46; discussion 157-8, 396-406, 2002.
- Osteen, KG, Bruner-Tran, KL, Keller, NR, Eisenberg, E Progesterone-mediated endometrial maturation limits matrix metalloproteinase (MMP) expression in an inflammatory-like environment: a regulatory system altered in endometriosis. Ann N Y Acad Sci, 95537-47; discussion 86-8, 396-406, 2002.
- Cornet PB, Picquet C, Lemoine P, Osteen KG, Bruner-Tran KL, Tabibzadeh S, Courtoy PJ, Eeckhout Y, Marbaix E, Henriet P "Regulation and function of LEFTY-A/EBAF in the human endometrium. mRNA expression during the menstrual cycle, control by progesterone, and effect on matrix metalloprotineases." Biol Chem , 27742496-42504, 2002.
- Bruner-Tran, Kaylon L, Eisenberg, Esther, Yeaman, Grant R, Anderson, Ted A, McBean, Judith, Osteen, Kevin G Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. J Clin Endocrinol Metab, 87(10), 4782-91, 2002.
- Curry TE Jr, Osteen KG "Cyclic changes in the matrix metalloproteinase system in the ovary and uterus." Biol Reprod, 641285-1296, 2001.
- Bofinger DP, Feng L, Chi LH, Love J, Stephen FD, Sutter TR, Osteen KG, Costich TG, Batt RE, Koury ST, Olson JR "Effect of TCDD exposure on CYP1A1 and CYP1B1 expression in explant cultures of human endometrium." Toxicol Sci, 62299-314, 2001.
- Keller, N R, Sierra-Rivera, E, Eisenberg, E, Osteen, K G Progesterone exposure prevents matrix metalloproteinase-3 (MMP-3) stimulation by interleukin-1alpha in human endometrial stromal cells. J Clin Endocrinol Metab, 85(4), 1611-9, 2000.
- Zheng, W L, Sierra-Rivera, E, Luan, J, Osteen, K G, Ong, D E Retinoic acid synthesis and expression of cellular retinol-binding protein and cellular retinoic acid-binding protein type II are concurrent with decidualization of rat uterine stromal cells. Endocrinology, 141(2), 802-8, 2000.
- Osteen, K G, Keller, N R, Feltus, F A, Melner, M H Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium. Gynecol Obstet Invest, 48 Suppl 12-13, 1999.
- Bruner, K L, Eisenberg, E, Gorstein, F, Osteen, K G Progesterone and transforming growth factor-beta coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis. Steroids, 64(9), 648-53, 1999.
- Zheng, W L, Bucco, R A, Sierra-Rievera, E, Osteen, K G, Melner, M H, Ong, D E Synthesis of retinoic acid by rat ovarian cells that express cellular retinoic acid-binding protein-II. Biol Reprod, 60(1), 110-4, 1999.
- Bruner-Tran, K L, Rier, S E, Eisenberg, E, Osteen, K G The potential role of environmental toxins in the pathophysiology of endometriosis. Gynecol Obstet Invest, 48 Suppl 145-56, 1999.
- Bucco, R A, Zheng, W L, Davis, J T, Sierra-Rivera, E, Osteen, K G, Chaudhary, A K, Ong, D E Cellular retinoic acid-binding protein(II) presence in rat uterine epithelial cells correlates with their synthesis of retinoic acid. Biochemistry, 36(13), 4009-14, 1997.
- Osteen, K G, Sierra-Rivera, E Does disruption of immune and endocrine systems by environmental toxins contribute to development of endometriosis. Semin Reprod Endocrinol, 15(3), 301-8, 1997.
- Osteen, K G, Sierra-Rivera, E, Keller, N R, Fox, D B Interleukin-1 alpha opposes progesterone-mediated suppression of MMP-7. A possible role of this cytokine during human implantation. Ann N Y Acad Sci, 828137-45, 1997.
- Bruner, K L, Matrisian, L M, Rodgers, W H, Gorstein, F, Osteen, K G Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest, 99(12), 2851-7, 1997.
- Bucco, R A, Zheng, W L, Wardlaw, S A, Davis, J T, Sierra-Rivera, E, Osteen, K G, Melner, M H, Kakkad, B P, Ong, D E Regulation and localization of cellular retinol-binding protein, retinol-binding protein, cellular retinoic acid-binding protein (CRABP), and CRABP II in the uterus of the pseudopregnant rat. Endocrinology, 137(7), 3111-22, 1996.
- Osteen, K G, Bruner, K L, Sharpe-Timms, K L Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis. Semin Reprod Endocrinol, 14(3), 247-55, 1996.
- Bruner, K L, Rodgers, W H, Gold, L I, Korc, M, Hargrove, J T, Matrisian, L M, Osteen, K G Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Natl Acad Sci U S A, 92(16), 7362-6, 1995.
- Matrisian, L M, Gaire, M, Rodgers, W H, Osteen, K G Metalloproteinase expression and hormonal regulation during tissue remodeling in the cycling human endometrium. Contrib Nephrol, 10794-100, 1994.
- Rodgers, WH, Matrisian, LM, Giudice, LC, Dsupin, B, Cannon, P, Svitek, C, Gorstein, F, and KG Osteen "Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroids." J. Clin. Invest., 94946-953, 1994.
- Osteen, K G, Rodgers, W H, Gaire, M, Hargrove, J T, Gorstein, F, Matrisian, L M Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc Natl Acad Sci U S A, 91(21), 10129-33, 1994.
- Bastias, MC, Kamijo, H, Osteen, KG Assessment of human sperm functional changes after in-vitro coincubation with cells retrieved from the human female reproductive tract. Hum Reprod, 8(10), 1670-7, 1993.
- Freeman, MR, Bastias, MC, Hill, GA, Osteen, KG Coculture of mouse embryos with cells isolated from the human ovarian follicle, oviduct, and uterine endometrium. Fertil Steril, 59(1), 138-42, 1993.
- Rodgers, W H, Osteen, K G, Matrisian, L M, Navre, M, Giudice, L C, Gorstein, F Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle. Am J Obstet Gynecol, 168(1 Pt 1), 253-60, 1993.
- Vasquez, JM, Eisenberg, E, Osteen, KG, Hickerson, D, Diamond, MP Laparoscopic ablation of endometriosis using the cavitational ultrasonic surgical aspirator. J Am Assoc Gynecol Laparosc, 1(1), 36-42, 1993.
- Osteen, KG, Anderson, TL, Schwartz, K, Hargrove, JT, Gorstein, F Distribution of tumor-associated glycoprotein-72 (TAG-72) expression throughout the normal female reproductive tract. Int J Gynecol Pathol, 11(3), 216-20, 1992.
- Hill, GA, Osteen, KG The effect of insulin on in vitro progesterone production of human granulosa cells. Int J Fertil, 37(2), 93-8, 1992.
- Osteen, KG, Anderson, TL Effect of estrogen on human endometrial epithelial cell growth and differentiation in vitro. Steroids, 56(5), 279-83, 1991.
- Osteen, KG, Anderson, TL, Hargrove, JT, Hill, GA, Gorstein, F Epithelial cells from normal human endometrium express a tumor-associated glycoprotein (TAG-72) epitope in vitro. Am J Obstet Gynecol, 163(2), 479-84, 1990.
- Anderson, TL, Gorstein, F, Osteen, KG Stromal-epithelial cell communication, growth factors, and tissue regulation. Lab Invest, 62(5), 519-21, 1990.
- Segars, JH, Hill, GA, Bryan, SH, Herbert, CM, Osteen, KG, Rogers, BJ, Wentz, AC The use of gonadotropin releasing hormone agonist (GnRHa) in good responders undergoing repeat in vitro fertilization/embryo transfer (IVF/ET). J In Vitro Fert Embryo Transf, 7(6), 327-31, 1990.
- Herbert, CM, Hill, GA, Maxson, WS, Wentz, AC, Osteen, KG Use of a sensitive urine pregnancy test before endometrial biopsies taken in the late luteal phase. Fertil Steril, 53(1), 162-4, 1990.
- Osteen, KG, Hill, GA, Hargrove, JT, Gorstein, F Development of a method to isolate and culture highly purified populations of stromal and epithelial cells from human endometrial biopsy specimens. Fertil Steril, 52(6), 965-72, 1989.
- Hill, GA, Osteen, KG Follicular fluid steroid content and in vitro steroid secretion by granulosa-lutein cells from individual follicles among different stimulation protocols for in vitro fertilization-embryo transfer. J In Vitro Fert Embryo Transf, 6(4), 201-6, 1989.
- Aleshire, SL, Osteen, KG, Maxson, WS, Entman, SS, Bradley, CA, Parl, FF Localization of transferrin and its receptor in ovarian follicular cells: morphologic studies in relation to follicular development. Fertil Steril, 51(3), 444-9, 1989.
- Blackburn, DG, Osteen, KG, Winfrey, VP, Hoffman, LH Obplacental giant cells of the domestic rabbit: development, morphology, and intermediate filament composition. J Morphol, 202(2), 185-203, 1989.
- Segars, JH, Niblack, GD, Osteen, KG, Rogers, BJ, Wentz, AC The human blastocyst produces a soluble factor(s) that interferes with lymphocyte proliferation. Fertil Steril, 52(3), 381-7, 1989.
- Hill, GA, Freeman, M, Bastias, MC, Rogers, BJ, Herbert, CM, Osteen, KG, Wentz, AC The influence of oocyte maturity and embryo quality on pregnancy rate in a program for in vitro fertilization-embryo transfer. Fertil Steril, 52(5), 801-6, 1989.
- Skinner, MK, Osteen, KG Developmental and hormonal regulation of bovine granulosa cell function in the preovulatory follicle. Endocrinology, 123(3), 1668-75, 1988.