Calcified Tissue International

, Volume 82, Issue 5, pp 383–391

Follicle-Stimulating Hormone Does Not Impact Male Bone Mass In Vivo or Human Male Osteoclasts In Vitro

  • Veronique Ritter
  • Barbara Thuering
  • Pierre Saint Mezard
  • Ngoc-Hong Luong-Nguyen
  • Yves Seltenmeyer
  • Uwe Junker
  • Brigitte Fournier
  • Mira Susa
  • Frederic Morvan


Bone loss in the elderly is mainly caused by osteoclast-induced bone resorption thought to be causally linked to the decline in estrogen and testosterone levels in females and males. Recently, involvement of follicle stimulating-hormone (FSH) in this process has been suggested to explain in part the etiology of the disease in females, whereas its role in males has never been examined. In this study, the direct impact of FSH on bone mass of 16-week-old C57BL/6J male mice by either daily intermittent application of 6 or 60 μg/kg of FSH or continuous delivery via miniosmotic pump of a dose of 6 μg/kg over the course of a month was assessed. Femoral peripheral quantitative computed tomographic and microcomputed tomographic analyses at 0, 2, and 4 weeks of FSH-treated mice did not reveal any differences in cancellous and cortical bone compared to sham-treated mice. FSH functionality was verified by demonstrating cAMP induction and activation of a cAMP-response element–containing reporter cell line by FSH. Furthermore, osteoclastogenesis from human mononuclear cell precursors and from RAW 264.7 cells was not affected by FSH (3, 10, 30 ng/mL) compared to control. No direct effect of FSH on gene regulation was observed by Affymetrix Gene Array on RAW 264.7 cells. Lastly, no expression of FSH receptor (FSHR) mRNA or FSHR was observed by quantitative polymerase chain reaction and Western blot in either human male osteoclasts or RAW 264.7 cells. These data show that FSH does not appear to modulate male bone mass regulation in vivo and does not act directly on osteoclastogenesis in vitro.


Osteoporosis Bone remodeling Follicle-stimulating hormone Osteoclast Mouse 


  1. 1.
    Bonnick SL (2006) Osteoporosis in men and women. Clin Cornerstone 8:28–39PubMedCrossRefGoogle Scholar
  2. 2.
    Zallone A (2006) Direct and indirect estrogen actions on osteoblasts and osteoclasts. Ann N Y Acad Sci 1068:173–179PubMedCrossRefGoogle Scholar
  3. 3.
    Legrand E, Audran M, Guggenbuhl P, Levasseur R, Chales G, Basle MF, Chappard D (2007) Trabecular bone microarchitecture is related to the number of risk factors and etiology in osteoporotic men. Microsc Res Tech 70:952–959PubMedCrossRefGoogle Scholar
  4. 4.
    Ebeling PR, Atley LM, Guthrie JR, Burger HG, Dennerstein L, Hopper JL, Wark JD (1996) Bone turnover markers and bone density across the menopausal transition. J Clin Endocrinol Metab 81:3366–3371PubMedCrossRefGoogle Scholar
  5. 5.
    Perrien DS, Achenbach SJ, Bledsoe SE, Walser B, Suva LJ, Khosla S, Gaddy D (2006) Bone turnover across the menopause transition: correlations with inhibins and follicle-stimulating hormone. J Clin Endocrinol Metab 91:1848–1854PubMedCrossRefGoogle Scholar
  6. 6.
    Sampath TK, Simic P, Sendak R, Draca N, Bowe AE, O’Brien S, Schiavi SC, McPherson JM, Vukicevic S (2007) Thyroid stimulating hormone (TSH) restores bone volume, microarchitecture and strength in aged ovariectomized rats. J Bone Miner Res 6:849–859CrossRefGoogle Scholar
  7. 7.
    Sun LI, Davies TF, Blair HC, Abe E, Zaidi M (2006) TSH and bone loss. Ann N Y Acad Sci 1068:309–318PubMedCrossRefGoogle Scholar
  8. 8.
    Abe E, Marians RC, Yu W, Wu XB, Ando T, Li Y, Iqbal J, Eldeiry L, Rajendren G, Blair HC, Davies TF, Zaidi M (2003) TSH is a negative regulator of skeletal remodeling. Cell 115:151–162PubMedCrossRefGoogle Scholar
  9. 9.
    Yarram SJ, Perry MJ, Christopher TJ, Westby K, Brown NL, Lamminen T, Rulli SB, Zhang FP, Huhtaniemi I, Sandy JR, Mansell JP (2003) Luteinizing hormone receptor knockout (LuRKO) mice and transgenic human chorionic gonadotropin (hCG)-overexpressing mice (hCGαß+) have bone phenotypes. Endocrinology 144:3555–3564PubMedCrossRefGoogle Scholar
  10. 10.
    Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, Papachristou DJ, Zaidi S, Zhu LL, Yaroslavskiy BB, Zhou H, Zallone A, Sairam MR, Kumar TR, Bo W, Braun J, Cardoso-Landa L, Schaffler MB, Moonga BS, Blair HC, Zaidi M (2006) FSH directly regulates bone mass. Cell 125:247–260PubMedCrossRefGoogle Scholar
  11. 11.
    Iqbal J, Sun L, Kumar TR, Blair HC, Zaidi M (2006) Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Natl Acad Sci USA 103:14925–14930PubMedCrossRefGoogle Scholar
  12. 12.
    Gao J, Tiwari-Pandey R, Samadfam R, Yang Y, Miao D, Karaplis AC, Sairam MR, Goltzman D (2007) Altered ovarian function affects skeletal homeostasis independent of the action of follicle-stimulating hormone. Endocrinology 148:2613–2621PubMedCrossRefGoogle Scholar
  13. 13.
    Gennari L, Bilezikian JP (2007) Osteoporosis in men. Endocrinol Metab Clin North Am 36:399–419PubMedCrossRefGoogle Scholar
  14. 14.
    Lunenfeld B (2006) Endocrinology of the aging male. Minerva Ginecol 58:153–170PubMedGoogle Scholar
  15. 15.
    Gasser JA (1995) Assessing bone quantity by pQCT. Bone 17:S145–S154Google Scholar
  16. 16.
    Kapadia RD, Stroup GB, Badger AM, Koller B, Levin JM, Coatney RW, Dodds RA, Liang X, Lark MW, Gowen M (1998) Applications of micro-CT and MR microscopy to study pre-clinical models of osteoporosis and osteoarthritis. Technol Health Care 6:361–372PubMedGoogle Scholar
  17. 17.
    Ruegsegger P, Koller B, Muller R (1996) A microtomographic system for the nondestructive evaluation of bone architecture. Calcif Tissue Int 58:24–29PubMedCrossRefGoogle Scholar
  18. 18.
    Susa M, Luong-Nguyen NH, Cappellen D, Zamurovic N, Gamse R (2004) Human primary osteoclasts: in vitro generation and applications as pharmacological and clinical assay. J Translational Med 2:6CrossRefGoogle Scholar
  19. 19.
    Fluhmann B, Zimmermann U, Muff R, Bilbe G, Fischer JA, Born W (1998) Parathyroid hormone responses of cyclic AMP-, serum- and phorbol ester-responsive reporter genes in osteoblast-like UMR-106 cells. Mol Cell Endocrinol 139:89–98PubMedCrossRefGoogle Scholar
  20. 20.
    Heber S, Sick B (2006) Quality assessment of Affymetrix GeneChip data. OMICS 10:358–368PubMedCrossRefGoogle Scholar
  21. 21.
    Szustakowski JD, Lee JH, Marrese CA, Kosinski PA, Nirmala NR, Kemp DM (2006) Identification of novel pathway regulation during myogenic differentiation. Genomics 87:129–138PubMedCrossRefGoogle Scholar
  22. 22.
    Bogovich K (1992) Follicle-stimulating hormone plays a role in the induction of ovarian follicular cysts in hypophysectomized rats. Biol Reprod 47:149–161PubMedCrossRefGoogle Scholar
  23. 23.
    Takase M, Tsutsui K, Kawashima S (1990) Effects of PRL and FSH on LH binding and number of Leydig cells in hypophysectomized mice. Endocrinol Jpn 37:193–203PubMedGoogle Scholar
  24. 24.
    Means AR, Dedman JR, Tash JS, Tindall DJ, van SM, Welsh MJ (1980) Regulation of the testis sertoli cell by follicle stimulating hormone. Annu Rev Physiol 42:59–70Google Scholar
  25. 25.
    Pacifici R (1996) Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 11:1043–1051PubMedGoogle Scholar
  26. 26.
    Miyaura C, Toda K, Inada M, Ohshiba T, Matsumoto C, Okada T, Ito M, Shizuta Y, Ito A (2001) Sex- and age-related response to aromatase deficiency in bone. Biochem Biophys Res Commun 280:1062–1068PubMedCrossRefGoogle Scholar
  27. 27.
    Chen MM, Yeh JK, Aloia JF (1995) Effect of ovariectomy on cancellous bone in the hypophysectomized rat. J Bone Miner Res 10:1334–1342PubMedCrossRefGoogle Scholar
  28. 28.
    DePaolo LV (1991) Hypersecretion of follicle-stimulating hormone (FSH) after ovariectomy of hypophysectomized, pituitary-grafted rats: implications for local regulatory control of FSH. Endocrinology 128:1731–1740PubMedCrossRefGoogle Scholar
  29. 29.
    Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR (2000) Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice. Endocrinology 141:4295–4308PubMedCrossRefGoogle Scholar
  30. 30.
    Britt KL, Drummond AE, Dyson M, Wreford NG, Jones MEE, Simpson ER, Findlay JK (2001) The ovarian phenotype of the aromatase knockout (ArKO) mouse. J Steroid Biochem Mol Biol 79:181–185PubMedCrossRefGoogle Scholar
  31. 31.
    Balla A, Danilovich N, Yang Y, Sairam MR (2003) Dynamics of ovarian development in the FORKO immature mouse: structural and functional implications for ovarian reserve. Biol Reprod 69:1281–1293PubMedCrossRefGoogle Scholar
  32. 32.
    Abel MH, Huhtaniemi I, Pakarinen P, Kumar TR, Charlton HM (2003) Age-related uterine and ovarian hypertrophy in FSH receptor knockout and FSHbeta subunit knockout mice. Reproduction 125:165–173PubMedCrossRefGoogle Scholar
  33. 33.
    Simoni M, Weinbauer GF, Gromoll J, Nieschlag E (1999) Role of FSH in male gonadal function. Ann Endocrinol (Paris) 60:102–106Google Scholar
  34. 34.
    Simoni M, Gromoll J, Nieschlag E (1997) The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev 18:739–773PubMedCrossRefGoogle Scholar
  35. 35.
    Sohn J, Youn H, Jeoung M, Koo Y, Yi C, Ji I, Ji TH (2003) Orientation of follicle-stimulating hormone (FSH) subunits complexed with the FSH receptor ß subunit toward the N terminus of exodomain and α subunit to exoloop 3. J Biol Chem 278:47868–47876PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Veronique Ritter
    • 1
  • Barbara Thuering
    • 1
  • Pierre Saint Mezard
    • 2
  • Ngoc-Hong Luong-Nguyen
    • 1
  • Yves Seltenmeyer
    • 1
  • Uwe Junker
    • 1
  • Brigitte Fournier
    • 1
  • Mira Susa
    • 1
  • Frederic Morvan
    • 1
  1. 1.Musculoskeletal Disease AreaNovartis Institutes for Biomedical ResearchBaselSwitzerland
  2. 2.BioinformaticsNovartis Institutes for Biomedical ResearchBaselSwitzerland

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