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. 1996 Apr 1;97(7):1732–1740. doi: 10.1172/JCI118600

Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence.

R L Jilka 1, R S Weinstein 1, K Takahashi 1, A M Parfitt 1, S C Manolagas 1
PMCID: PMC507238  PMID: 8601639

Abstract

Bone marrow is the principal site for osteoclastogenesis and osteoblastogenesis; and an increase in the former has been linked with bone loss caused by acute loss of gonadal steroids. We have now used an established murine model of accelerated senescence and osteopenia (SAMP6) to test the hypothesis that reduced osteoblastogenesis is linked with decreased bone mass. At 1 mo of age, the number of osteoblast progenitors in SAMP6 marrow was indistinguishable from controls; however a threefold decrease was found at 3-4 mo of age. Impaired osteoblast formation was temporally associated with decreased bone formation and decreased bone mineral density, as determined by histomorphometric analysis of tetracycline-labeled cancellous bone and dual-energy x-ray absorptiometry, respectively. Osteoclastogenesis determined in ex vivo bone marrow cultures was also decreased in these mice, as was the number of osteoclasts in histologic sections. Moreover, unlike controls, senescence-accelerated mice failed to increase osteoclast development after gonadectomy. The osteoclastogenesis defeat was secondary to impaired osteoblast formation as evidenced by the fact that osteoclastogenesis could be restored by addition of osteoblastic cells from normal mice. These findings provide the first demonstration of a link between low bone mineral density and decreased osteoblastogenesis in the bone marrow and validate the senescence-accelerated mouse as a model of involutional osteopenia.

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Selected References

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  1. Balena R., Toolan B. C., Shea M., Markatos A., Myers E. R., Lee S. C., Opas E. E., Seedor J. G., Klein H., Frankenfield D. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest. 1993 Dec;92(6):2577–2586. doi: 10.1172/JCI116872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bellido T., Jilka R. L., Boyce B. F., Girasole G., Broxmeyer H., Dalrymple S. A., Murray R., Manolagas S. C. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. J Clin Invest. 1995 Jun;95(6):2886–2895. doi: 10.1172/JCI117995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Eastell R., Yergey A. L., Vieira N. E., Cedel S. L., Kumar R., Riggs B. L. Interrelationship among vitamin D metabolism, true calcium absorption, parathyroid function, and age in women: evidence of an age-related intestinal resistance to 1,25-dihydroxyvitamin D action. J Bone Miner Res. 1991 Feb;6(2):125–132. doi: 10.1002/jbmr.5650060205. [DOI] [PubMed] [Google Scholar]
  4. Eriksen E. F., Hodgson S. F., Eastell R., Cedel S. L., O'Fallon W. M., Riggs B. L. Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J Bone Miner Res. 1990 Apr;5(4):311–319. doi: 10.1002/jbmr.5650050402. [DOI] [PubMed] [Google Scholar]
  5. Falla N., Van Vlasselaer, Bierkens J., Borremans B., Schoeters G., Van Gorp U. Characterization of a 5-fluorouracil-enriched osteoprogenitor population of the murine bone marrow. Blood. 1993 Dec 15;82(12):3580–3591. [PubMed] [Google Scholar]
  6. Gallagher J. C., Goldgar D., Moy A. Total bone calcium in normal women: effect of age and menopause status. J Bone Miner Res. 1987 Dec;2(6):491–496. doi: 10.1002/jbmr.5650020605. [DOI] [PubMed] [Google Scholar]
  7. Girasole G., Jilka R. L., Passeri G., Boswell S., Boder G., Williams D. C., Manolagas S. C. 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest. 1992 Mar;89(3):883–891. doi: 10.1172/JCI115668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Girasole G., Passeri G., Jilka R. L., Manolagas S. C. Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest. 1994 Apr;93(4):1516–1524. doi: 10.1172/JCI117130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Heaney R. P. Estrogen-calcium interactions in the postmenopause: a quantitative description. Bone Miner. 1990 Oct;11(1):67–84. doi: 10.1016/0169-6009(90)90016-9. [DOI] [PubMed] [Google Scholar]
  10. Jilka R. L., Hangoc G., Girasole G., Passeri G., Williams D. C., Abrams J. S., Boyce B., Broxmeyer H., Manolagas S. C. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992 Jul 3;257(5066):88–91. doi: 10.1126/science.1621100. [DOI] [PubMed] [Google Scholar]
  11. Kitado H., Higuchi K., Takeda T. Molecular genetic characterization of the senescence-accelerated mouse (SAM) strains. J Gerontol. 1994 Nov;49(6):B247–B254. doi: 10.1093/geronj/49.6.b247. [DOI] [PubMed] [Google Scholar]
  12. Korzeniewski C., Callewaert D. M. An enzyme-release assay for natural cytotoxicity. J Immunol Methods. 1983 Nov 25;64(3):313–320. doi: 10.1016/0022-1759(83)90438-6. [DOI] [PubMed] [Google Scholar]
  13. Lindsay R., Hart D. M., Forrest C., Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet. 1980 Nov 29;2(8205):1151–1154. doi: 10.1016/s0140-6736(80)92592-1. [DOI] [PubMed] [Google Scholar]
  14. Lips P., Courpron P., Meunier P. J. Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res. 1978 Nov 10;26(1):13–17. doi: 10.1007/BF02013227. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Matsushita M., Tsuboyama T., Kasai R., Okumura H., Yamamuro T., Higuchi K., Higuchi K., Kohno A., Yonezu T., Utani A. Age-related changes in bone mass in the senescence-accelerated mouse (SAM). SAM-R/3 and SAM-P/6 as new murine models for senile osteoporosis. Am J Pathol. 1986 Nov;125(2):276–283. [PMC free article] [PubMed] [Google Scholar]
  17. McKenna M. J. Differences in vitamin D status between countries in young adults and the elderly. Am J Med. 1992 Jul;93(1):69–77. doi: 10.1016/0002-9343(92)90682-2. [DOI] [PubMed] [Google Scholar]
  18. Nordin B. E., Need A. G., Bridges A., Horowitz M. Relative contributions of years since menopause, age, and weight to vertebral density in postmenopausal women. J Clin Endocrinol Metab. 1992 Jan;74(1):20–23. doi: 10.1210/jcem.74.1.1727821. [DOI] [PubMed] [Google Scholar]
  19. Orwoll E. S., Klein R. F. Osteoporosis in men. Endocr Rev. 1995 Feb;16(1):87–116. doi: 10.1210/edrv-16-1-87. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Parfitt A. M., Mathews C. H., Villanueva A. R., Kleerekoper M., Frame B., Rao D. S. Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest. 1983 Oct;72(4):1396–1409. doi: 10.1172/JCI111096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Parfitt A. M., Villanueva A. R., Foldes J., Rao D. S. Relations between histologic indices of bone formation: implications for the pathogenesis of spinal osteoporosis. J Bone Miner Res. 1995 Mar;10(3):466–473. doi: 10.1002/jbmr.5650100319. [DOI] [PubMed] [Google Scholar]
  23. Parisien M., Mellish R. W., Silverberg S. J., Shane E., Lindsay R., Bilezikian J. P., Dempster D. W. Maintenance of cancellous bone connectivity in primary hyperparathyroidism: trabecular strut analysis. J Bone Miner Res. 1992 Aug;7(8):913–919. doi: 10.1002/jbmr.5650070808. [DOI] [PubMed] [Google Scholar]
  24. Poli V., Balena R., Fattori E., Markatos A., Yamamoto M., Tanaka H., Ciliberto G., Rodan G. A., Costantini F. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 1994 Mar 1;13(5):1189–1196. doi: 10.1002/j.1460-2075.1994.tb06368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sherman S. S., Tobin J. D., Hollis B. W., Gundberg C. M., Roy T. A., Plato C. C. Biochemical parameters associated with low bone density in healthy men and women. J Bone Miner Res. 1992 Oct;7(10):1123–1130. doi: 10.1002/jbmr.5650071003. [DOI] [PubMed] [Google Scholar]
  26. Steiniche T., Hasling C., Charles P., Eriksen E. F., Mosekilde L., Melsen F. A randomized study on the effects of estrogen/gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis. Bone. 1989;10(5):313–320. doi: 10.1016/8756-3282(89)90126-9. [DOI] [PubMed] [Google Scholar]
  27. Takahashi N., Akatsu T., Udagawa N., Sasaki T., Yamaguchi A., Moseley J. M., Martin T. J., Suda T. Osteoblastic cells are involved in osteoclast formation. Endocrinology. 1988 Nov;123(5):2600–2602. doi: 10.1210/endo-123-5-2600. [DOI] [PubMed] [Google Scholar]
  28. Takeda T., Hosokawa M., Higuchi K., Hosono M., Akiguchi I., Katoh H. A novel murine model of aging, Senescence-Accelerated Mouse (SAM). Arch Gerontol Geriatr. 1994 Sep-Oct;19(2):185–192. doi: 10.1016/0167-4943(94)90039-6. [DOI] [PubMed] [Google Scholar]
  29. Tsai K. S., Wahner H. W., Offord K. P., Melton L. J., 3rd, Kumar R., Riggs B. L. Effect of aging on vitamin D stores and bone density in women. Calcif Tissue Int. 1987 May;40(5):241–243. doi: 10.1007/BF02555255. [DOI] [PubMed] [Google Scholar]
  30. Weinstein R. S., Bell N. H. Diminished rates of bone formation in normal black adults. N Engl J Med. 1988 Dec 29;319(26):1698–1701. doi: 10.1056/NEJM198812293192603. [DOI] [PubMed] [Google Scholar]
  31. Weinstein R. S. Decreased mineralization in hemodialysis patients after subtotal parathyroidectomy. Calcif Tissue Int. 1982 Jan;34(1):16–20. doi: 10.1007/BF02411202. [DOI] [PubMed] [Google Scholar]
  32. Weinstein R. S., Underwood J. L., Hutson M. S., DeLuca H. F. Bone histomorphometry in vitamin D-deficient rats infused with calcium and phosphorus. Am J Physiol. 1984 Jun;246(6 Pt 1):E499–E505. doi: 10.1152/ajpendo.1984.246.6.E499. [DOI] [PubMed] [Google Scholar]

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