Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Nov 15;98(10):2351–2357. doi: 10.1172/JCI119047

Estrogen suppresses activation but enhances formation phase of osteogenic response to mechanical stimulation in rat bone.

C J Jagger 1, J W Chow 1, T J Chambers 1
PMCID: PMC507686  PMID: 8941653

Abstract

We used a model whereby mechanical stimulation induces bone formation in rat caudal vertebrae, to test the effect of estrogen on this osteogenic response. Unexpectedly, estrogen administered daily throughout the experiments (8-11 d) suppressed, and ovariectomy enhanced, mechanically induced osteogenesis. Osteogenesis was unaffected by the resorption-inhibitor pamidronate, suggesting that the suppression of bone formation caused by estrogen was not due to suppression of resorption. We found that estrogen did not significantly reduce the proportion of osteocytes that were induced by mechanical stimulation to express c-fos and IGF-I mRNA; and estrogen suppressed mechanically induced osteogenesis whether administration was started 24 h before or 24 h after loading. This suggests that estrogen acts primarily not on the strain-sensing mechanism itself, but on the osteogenic response to signals generated by strain-sensitive cells. We also found that when estrogen administration was started 3 d after mechanical stimulation, by which time osteogenesis is established, estrogen augmented the osteogenic response. This data is consistent with in vitro evidence for estrogen responsiveness in two phenotypically distinct bone cell types: stromal cells, whose functional activities are suppressed, and osteoblasts, which are stimulated, by estrogen.

Full Text

The Full Text of this article is available as a PDF (212.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abe T., Chow J. W., Lean J. M., Chambers T. J. Estrogen does not restore bone lost after ovariectomy in the rat. J Bone Miner Res. 1993 Jul;8(7):831–838. doi: 10.1002/jbmr.5650080709. [DOI] [PubMed] [Google Scholar]
  2. Bellido T., Girasole G., Passeri G., Yu X. P., Mocharla H., Jilka R. L., Notides A., Manolagas S. C. Demonstration of estrogen and vitamin D receptors in bone marrow-derived stromal cells: up-regulation of the estrogen receptor by 1,25-dihydroxyvitamin-D3. Endocrinology. 1993 Aug;133(2):553–562. doi: 10.1210/endo.133.2.8393768. [DOI] [PubMed] [Google Scholar]
  3. Cheng M. Z., Zaman G., Rawlinson S. C., Suswillo R. F., Lanyon L. E. Mechanical loading and sex hormone interactions in organ cultures of rat ulna. J Bone Miner Res. 1996 Apr;11(4):502–511. doi: 10.1002/jbmr.5650110411. [DOI] [PubMed] [Google Scholar]
  4. Chow J. W., Badve S., Chambers T. J. Bone formation is not coupled to bone resorption in a site-specific manner in adult rats. Anat Rec. 1993 Jun;236(2):366–372. doi: 10.1002/ar.1092360210. [DOI] [PubMed] [Google Scholar]
  5. Chow J. W., Jagger C. J., Chambers T. J. Characterization of osteogenic response to mechanical stimulation in cancellous bone of rat caudal vertebrae. Am J Physiol. 1993 Aug;265(2 Pt 1):E340–E347. doi: 10.1152/ajpendo.1993.265.2.E340. [DOI] [PubMed] [Google Scholar]
  6. Chow J., Tobias J. H., Colston K. W., Chambers T. J. Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation. J Clin Invest. 1992 Jan;89(1):74–78. doi: 10.1172/JCI115588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Christiansen C., Christensen M. S., McNair P., Hagen C., Stocklund K. E., Transbøl I. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Eur J Clin Invest. 1980 Aug;10(4):273–279. doi: 10.1111/j.1365-2362.1980.tb00033.x. [DOI] [PubMed] [Google Scholar]
  8. Cowin S. C., Moss-Salentijn L., Moss M. L. Candidates for the mechanosensory system in bone. J Biomech Eng. 1991 May;113(2):191–197. doi: 10.1115/1.2891234. [DOI] [PubMed] [Google Scholar]
  9. Curran T., Gordon M. B., Rubino K. L., Sambucetti L. C. Isolation and characterization of the c-fos(rat) cDNA and analysis of post-translational modification in vitro. Oncogene. 1987;2(1):79–84. [PubMed] [Google Scholar]
  10. Edwards M. W., Bain S. D., Bailey M. C., Lantry M. M., Howard G. A. 17 beta estradiol stimulation of endosteal bone formation in the ovariectomized mouse: an animal model for the evaluation of bone-targeted estrogens. Bone. 1992;13(1):29–34. doi: 10.1016/8756-3282(92)90358-4. [DOI] [PubMed] [Google Scholar]
  11. Ernst M., Heath J. K., Rodan G. A. Estradiol effects on proliferation, messenger ribonucleic acid for collagen and insulin-like growth factor-I, and parathyroid hormone-stimulated adenylate cyclase activity in osteoblastic cells from calvariae and long bones. Endocrinology. 1989 Aug;125(2):825–833. doi: 10.1210/endo-125-2-825. [DOI] [PubMed] [Google Scholar]
  12. Ernst M., Schmid C., Froesch E. R. Enhanced osteoblast proliferation and collagen gene expression by estradiol. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2307–2310. doi: 10.1073/pnas.85.7.2307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Frost H. M. Vital biomechanics: proposed general concepts for skeletal adaptations to mechanical usage. Calcif Tissue Int. 1988 Mar;42(3):145–156. doi: 10.1007/BF02556327. [DOI] [PubMed] [Google Scholar]
  14. Gleeson P. B., Protas E. J., LeBlanc A. D., Schneider V. S., Evans H. J. Effects of weight lifting on bone mineral density in premenopausal women. J Bone Miner Res. 1990 Feb;5(2):153–158. doi: 10.1002/jbmr.5650050208. [DOI] [PubMed] [Google Scholar]
  15. Jagger C. J., Chambers T. J., Chow J. W. Stimulation of bone formation by dynamic mechanical loading of rat caudal vertebrae is not suppressed by 3-amino-1-hydroxypropylidene-1-bisphosphonate (AHPrBP). Bone. 1995 Mar;16(3):309–313. doi: 10.1016/8756-3282(94)00043-3. [DOI] [PubMed] [Google Scholar]
  16. Jaworski Z. F. Coupling of bone formation to bone resorption: a broader view. Calcif Tissue Int. 1984 Sep;36(5):531–535. doi: 10.1007/BF02405360. [DOI] [PubMed] [Google Scholar]
  17. Kalu D. N. The ovariectomized rat model of postmenopausal bone loss. Bone Miner. 1991 Dec;15(3):175–191. doi: 10.1016/0169-6009(91)90124-i. [DOI] [PubMed] [Google Scholar]
  18. Kitazawa R., Kimble R. B., Vannice J. L., Kung V. T., Pacifici R. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest. 1994 Dec;94(6):2397–2406. doi: 10.1172/JCI117606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Komm B. S., Terpening C. M., Benz D. J., Graeme K. A., Gallegos A., Korc M., Greene G. L., O'Malley B. W., Haussler M. R. Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells. Science. 1988 Jul 1;241(4861):81–84. doi: 10.1126/science.3164526. [DOI] [PubMed] [Google Scholar]
  20. Lanyon L. E. Functional strain as a determinant for bone remodeling. Calcif Tissue Int. 1984;36 (Suppl 1):S56–S61. doi: 10.1007/BF02406134. [DOI] [PubMed] [Google Scholar]
  21. Lanyon L. E. The success and failure of the adaptive response to functional load-bearing in averting bone fracture. Bone. 1992;13 (Suppl 2):S17–S21. doi: 10.1016/8756-3282(92)90191-x. [DOI] [PubMed] [Google Scholar]
  22. Lean J. M., Chow J. W., Chambers T. J. The rate of cancellous bone formation falls immediately after ovariectomy in the rat. J Endocrinol. 1994 Jul;142(1):119–125. doi: 10.1677/joe.0.1420119. [DOI] [PubMed] [Google Scholar]
  23. Lean J. M., Jagger C. J., Chambers T. J., Chow J. W. Increased insulin-like growth factor I mRNA expression in rat osteocytes in response to mechanical stimulation. Am J Physiol. 1995 Feb;268(2 Pt 1):E318–E327. doi: 10.1152/ajpendo.1995.268.2.E318. [DOI] [PubMed] [Google Scholar]
  24. Lean J. M., Mackay A. G., Chow J. W., Chambers T. J. Osteocytic expression of mRNA for c-fos and IGF-I: an immediate early gene response to an osteogenic stimulus. Am J Physiol. 1996 Jun;270(6 Pt 1):E937–E945. doi: 10.1152/ajpendo.1996.270.6.E937. [DOI] [PubMed] [Google Scholar]
  25. Lin B. Y., Jee W. S., Chen M. M., Ma Y. F., Ke H. Z., Li X. J. Mechanical loading modifies ovariectomy-induced cancellous bone loss. Bone Miner. 1994 Jun;25(3):199–210. doi: 10.1016/s0169-6009(08)80239-5. [DOI] [PubMed] [Google Scholar]
  26. Lindsay R., Hart D. M., Aitken J. M., MacDonald E. B., Anderson J. B., Clarke A. C. Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet. 1976 May 15;1(7968):1038–1041. doi: 10.1016/s0140-6736(76)92217-0. [DOI] [PubMed] [Google Scholar]
  27. Malluche H. H., Faugere M. C., Rush M., Friedler R. Osteoblastic insufficiency is responsible for maintenance of osteopenia after loss of ovarian function in experimental beagle dogs. Endocrinology. 1986 Dec;119(6):2649–2654. doi: 10.1210/endo-119-6-2649. [DOI] [PubMed] [Google Scholar]
  28. Manolagas S. C., Jilka R. L. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 1995 Feb 2;332(5):305–311. doi: 10.1056/NEJM199502023320506. [DOI] [PubMed] [Google Scholar]
  29. Murphy L. J., Bell G. I., Duckworth M. L., Friesen H. G. Identification, characterization, and regulation of a rat complementary deoxyribonucleic acid which encodes insulin-like growth factor-I. Endocrinology. 1987 Aug;121(2):684–691. doi: 10.1210/endo-121-2-684. [DOI] [PubMed] [Google Scholar]
  30. Nordin B. E., MacGregor J., Smith D. A. The incidence of osteoporosis in normal women: its relation to age and the menopause. Q J Med. 1966 Jan;35(137):25–38. [PubMed] [Google Scholar]
  31. Notelovitz M., Martin D., Tesar R., Khan F. Y., Probart C., Fields C., McKenzie L. Estrogen therapy and variable-resistance weight training increase bone mineral in surgically menopausal women. J Bone Miner Res. 1991 Jun;6(6):583–590. doi: 10.1002/jbmr.5650060609. [DOI] [PubMed] [Google Scholar]
  32. Parfitt A. M., Drezner M. K., Glorieux F. H., Kanis J. A., Malluche H., Meunier P. J., Ott S. M., Recker R. R. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987 Dec;2(6):595–610. doi: 10.1002/jbmr.5650020617. [DOI] [PubMed] [Google Scholar]
  33. Parfitt A. M. The cellular basis of bone remodeling: the quantum concept reexamined in light of recent advances in the cell biology of bone. Calcif Tissue Int. 1984;36 (Suppl 1):S37–S45. doi: 10.1007/BF02406132. [DOI] [PubMed] [Google Scholar]
  34. Pead M. J., Skerry T. M., Lanyon L. E. Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading. J Bone Miner Res. 1988 Dec;3(6):647–656. doi: 10.1002/jbmr.5650030610. [DOI] [PubMed] [Google Scholar]
  35. Rodan G. A. Mechanical loading, estrogen deficiency, and the coupling of bone formation to bone resorption. J Bone Miner Res. 1991 Jun;6(6):527–530. doi: 10.1002/jbmr.5650060602. [DOI] [PubMed] [Google Scholar]
  36. Rubin C. T., Lanyon L. E. Dynamic strain similarity in vertebrates; an alternative to allometric limb bone scaling. J Theor Biol. 1984 Mar 21;107(2):321–327. doi: 10.1016/s0022-5193(84)80031-4. [DOI] [PubMed] [Google Scholar]
  37. Turner C. H. Do estrogens increase bone formation? Bone. 1991;12(5):305–306. doi: 10.1016/8756-3282(91)90014-a. [DOI] [PubMed] [Google Scholar]
  38. Turner C. H. Homeostatic control of bone structure: an application of feedback theory. Bone. 1991;12(3):203–217. doi: 10.1016/8756-3282(91)90043-i. [DOI] [PubMed] [Google Scholar]
  39. Turner R. T., Colvard D. S., Spelsberg T. C. Estrogen inhibition of periosteal bone formation in rat long bones: down-regulation of gene expression for bone matrix proteins. Endocrinology. 1990 Sep;127(3):1346–1351. doi: 10.1210/endo-127-3-1346. [DOI] [PubMed] [Google Scholar]
  40. Whitson S. W. Estrogen-induced osteoid formation in the osteon of mature female rabbits. An electron-microscopic study. Anat Rec. 1972 Aug;173(4):417–435. doi: 10.1002/ar.1091730404. [DOI] [PubMed] [Google Scholar]
  41. Wronski T. J., Cintrón M., Dann L. M. Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif Tissue Int. 1988 Sep;43(3):179–183. doi: 10.1007/BF02571317. [DOI] [PubMed] [Google Scholar]
  42. Wronski T. J., Dann L. M., Scott K. S., Crooke L. R. Endocrine and pharmacological suppressors of bone turnover protect against osteopenia in ovariectomized rats. Endocrinology. 1989 Aug;125(2):810–816. doi: 10.1210/endo-125-2-810. [DOI] [PubMed] [Google Scholar]
  43. Wronski T. J., Yen C. F., Scott K. S. Estrogen and diphosphonate treatment provide long-term protection against osteopenia in ovariectomized rats. J Bone Miner Res. 1991 Apr;6(4):387–394. doi: 10.1002/jbmr.5650060410. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES