The major focus of this application will be to use cultured normal human osteoblast-like (hOB) cells as a model system for understanding the regulation of normal osteoblast function and to provide insights on abnormal cell function in osteoporosis. Studies to develop a defined, serum-free medium for optimal cell growth will be continued since this medium should 1) enhance the production of these cells which are slow growing, labor intensive and costly, and 2) permit more accurate assessment of the effects of individual growth related agents on these cells. Our present data demonstrate the presence of estrogen receptors in hOB cells with indications of the presence of androgen and progesterone receptors. We plan to continue our analyses of the functional sex steroid receptors in the hOB cells and selected osteosarcoma lines using a nuclear binding assay, a charcoal assay, Northern blot (mRNA), and Western blot (protein) analyses. We have obtained cDNA probes to a variety of mRNAs for bone proteins, growth factors, proto-oncogenes and other steroid regulated genes including steroid receptors. We plan to screen these cDNA probes to select those which display optimal estrogen regulation. Then, using these cDNAs, we will assess in greater detail the effects of estrogens, androgens and progestins on the mRNA levels in hOB cells and in selected osteosarcoma cell lines. Studies of steroid agonism and antagonism with other sex steroids and other hormones (PTH, 1,25 dihydroxyvitamin D3, and glucocorticoids) will be performed in hOB cells. The steroid action on the levels of bone proteins will be measured in the instance the steroid regulation of the expression of these important genes occurs at the level of translation/post-translation. Finally, we plan to continue our investigations on the effects of sex steroids on the production of the transforming growth factors (TGF-a, TGF-b) and insulin-like growth factors (IGF-I adn IGF-II) in hOB cells at the level of mRNA, protein, and activity. Collaborations with Dr. Greg Mundy and coworkers, University of Texans at San Antonio, will involve studies of the interactions of estrogens with our sex steroids and with PTH to influence TGF-B production. Also in the same collaboration, the effects of conditioned media from estrogen treated hOB cells on osteoclast cell function (bone resorption) will be investigated. It is hoped that the above investigations will yield insights into bone regulatory pathways and ultimately into abnormalities of these [pathways in involutional osteoporosis resulting in better strategies for its treatment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Kattah, Andrea G; Smith, Carin Y; Gazzuola Rocca, Liliana et al. (2018) CKD in Patients with Bilateral Oophorectomy. Clin J Am Soc Nephrol 13:1649-1658
Khosla, Sundeep; Monroe, David G (2018) Regulation of Bone Metabolism by Sex Steroids. Cold Spring Harb Perspect Med 8:
Bower, James H; Grossardt, Brandon R; Rocca, Walter A et al. (2018) Prevalence of and indications for antipsychotic use in Parkinson's disease. Mov Disord 33:325-328
Rocca, Walter A; Grossardt, Brandon R; Brue, Scott M et al. (2018) Data Resource Profile: Expansion of the Rochester Epidemiology Project medical records-linkage system (E-REP). Int J Epidemiol 47:368-368j
Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256
Khosla, Sundeep; Farr, Joshua N; Kirkland, James L (2018) Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. J Clin Endocrinol Metab 103:1282-1290
Rocca, Walter A (2018) The future burden of Parkinson's disease. Mov Disord 33:8-9
Rocca, Walter A; Gazzuola Rocca, Liliana; Smith, Carin Y et al. (2018) Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: A population-based case-control study. Maturitas 117:64-77
Drake, Matthew T; Fenske, Jennifer S; Blocki, Frank A et al. (2018) Validation of a novel, rapid, high precision sclerostin assay not confounded by sclerostin fragments. Bone 111:36-43
Laughlin-Tommaso, Shannon K; Khan, Zaraq; Weaver, Amy L et al. (2018) Cardiovascular and metabolic morbidity after hysterectomy with ovarian conservation: a cohort study. Menopause 25:483-492

Showing the most recent 10 out of 401 publications