Skip to main content
SpringerLink
Log in

Stimulation of human osteoblast differentiation and function by ipriflavone and its metabolites

  • Laboratory Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Ipriflavone (IP), an isoflavone derivative, has been shown to interfere with bone remodeling by inhibiting bone resorption and perhaps stimulating bone formation. In this study, we have analyzed the effect of IP and its metabolites on the differentiation and function of human osteoblastic cells. Bone marrow stromal osteoprogenitor cells (BMC) and trabecular bone osteoblasts (HOB) were isolated from human donors. The former can be induced to differentiate by treatment with dexamethasone, whereas the latter represent a more differentiated osteoblast. Incubation of BMC with metabolite III (10-5 M) for 1 week induced modest but significant changes of alkaline phosphatase activity. Though both IP and metabolite III stimulated the expression of bone sialoprotein mRNA, a protein involved in cell attachment to the matrix, only metabolite III increased the steady-state level of decorin mRNA, a collagen fibrillogenesis-regulating proteoglycan. Metabolites III and V, but not the other isoflavones, increased the expression of type I collagen mRNA in HOB, whereas no detectable changes were observed in BMC cells with any of the experimental compounds. In HOB, an increased abundance of osteopontin and bone sialoprotein mRNA were also obtained after 1-week treatment with IP or metabolite V. No appreciable effects of IP or its metabolites were seen on osteocalcin expression and synthesis by either cell type. Finally, IP consistently increased the amount of 45Ca incorporated into the cell layer by BMC, and stimulated mineralization of both BMC and HOB, assessed by von Kossa staining. Thus, IP and its metabolites regulate the differentiation and biosynthetic properties of human bone-forming cells by enhancing the expression of some important matrix proteins and facilitating the mineralization process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Yamazaki I, Shino A, Shimizu Y, Tsukuda R, Shirakawa Y, Kinoshita M (1986) Effect of ipriflavone on glucocorticoid-induced osteoporosis in rats. Life Sci 38:951–958

    Google Scholar 

  2. Foldes I, Rapcsak M, Szoor A, Gyarmati J, Szilagy T (1988) The effect of ipriflavone treatment on osteoporosis induced by immobilization. Acta Morphol Hungarica 36:79–93

    Google Scholar 

  3. Shino A, Matsuo T, Tsuda M, Yamazaki I, Tsukuda R, Kitazaki T, Shiota K, Okada H, Yoshida K (1986) Effect of ipriflavone on bone and mineral metabolism in the streptozotocin diabetic rats. J Bone Miner Metab 3:27–37

    Google Scholar 

  4. Agnusdei D, Bufalino L, Gennari C (1993) Effects of ipriflavone on bone mass and bone turnover in postmenopausal women with low bone mass. In: Christiansen C, Riis BJ (eds) Proceedings 1993: IV International Symposium on Osteoporosis. Handelstrykkeriet, Aalborg, Denmark, pp 467–470

    Google Scholar 

  5. Passeri M, Abate G, Costi D, Biondi M, Di Peppe C, Bufalino L, Castiglione GN (1993) Ipriflavone in the treatment of established postmenopausal osteoporosis. In: Christiansen C, Riis BJ (eds) Proceedings 1993: IV International Symposium on Osteoporosis. Handelstrykkeriet, Aalborg, Denmark, pp 463–466

    Google Scholar 

  6. Gambacciani M, Spinetti A, Cappagli B, Taponeco F, Felipetto R, Parrini D, Cappelli N, Fioretti P (1993) Effects of ipriflavone administration on bone mass and metabolism in ovariectomized women. J Endocrinol Invest 16:333–337

    Google Scholar 

  7. Agnusdei D, Camporeale A, Gonnelli S, Gennari C, Baroni MC, Passeri M (1992) Short-term treatment of Paget's disease on bone with ipriflavone. Bone Miner 19:S35-S42

    Google Scholar 

  8. Mazzuoli G, Romagnoli E, Carnevale V, Scarda A, Scarnecchia L, Pacitti MT, Rosso R, Minisola S (1992) Effects of ipriflavone on bone remodeling in primary hyperparathyroidism. Bone Miner 19:S27-S33

    Google Scholar 

  9. Notoya K, Yoshida K, Taketomi S, Yamazaki I, Kumegawa M (1992) Inhibitory effect of ipriflavone on pit formation in mouse unfractioned bone cells. Calcif Tissue Int 51:S3-S6

    Google Scholar 

  10. Morita I, Sakagushi K, Kurachi T, Murota S (1992) Ipriflavone inhibits murine osteoclast formation in vitro. Calcif Tissue Int 51:S7-S10

    Google Scholar 

  11. Bonucci E, Silvestrini G, Ballanti P, Masi L, Franchi A, Bufalino L, Brandi ML (1992) Cytological and ultrastructural investigation of osteoblastic and preosteoclastic cells grown in vitro in the presence of ipriflavone: preliminary results. Bone Miner 19:S15-S25

    Google Scholar 

  12. Bonucci E, Ballanti P, Martelli A, Mereto E, Brambilla G, Bianco P, Bufalino L (1992) Ipriflavone inhibits osteoclast differentiation in parathyroid transplanted parietal bone of rats. Calcif Tissue Int 50:314–319

    Google Scholar 

  13. Azria M, Behar C, Cooper S (1993) Lack of effect of ipriflavone on osteoclast motility and bone resorption in in vitro and ex vivo studies. Calcif Tissue Int 52:16–20

    Google Scholar 

  14. Sziklai I, Ribari O (1985) The effect of flavone treatment on human otosclerotic ossicle organ cultures. Arch Otorhinolaryngol 242:67–70

    Google Scholar 

  15. Ribari O, Sziklai I (1987) Effect of flavonoid on PGE2-induced alterations in percentage collagen synthesis in ossicle organ cultures. Acta Otolaryngol 103:657–660

    Google Scholar 

  16. Benvenuti S, Tanini A, Frediani U, Bianchi S, Masi L, Casano R, Bufalino L, Serio M, Brandi ML (1991) Effects of ipriflavone and its metabolites on a clonal osteoblastic cell line. J Bone Miner Res 6:987–996

    Google Scholar 

  17. Notoya K, Tsukuda R, Yoshida K, Taketomi S (1992) Stimulatory effect of ipriflavone on formation of bone-like tissue in rat bone marrow stromal cell culture. Calcif Tissue Int 51:S16-S20

    Google Scholar 

  18. Notoya K, Yoshida K, Tsukuda R, Taketomi S (1994) Effect of ipriflavone on expression of markers characteristic of the osteoblast phenotype in rat bone marrow stromal cell culture. J Bone Miner Res 9:395–400

    Google Scholar 

  19. Kakai Y, Kawase T, Nakano T, Mikuni-Takagaki Y, Saito S (1992) Effect of ipriflavone and estrogen on the differentiation and proliferation of osteogenic cells. Calcif Tissue Int 51:S11-S15

    Google Scholar 

  20. Cheng S, Yang JW, Rifas L, Zhang S, Avioli LV (1994) Differentiation of human bone marrow osteogenic stromal cells in vitro: induction of the osteoblast phenotype by dexamethasone. Endocrinology 134:277–286

    Google Scholar 

  21. Gehron Robey P, Termine JD (1985) Human bone cells in vitro. Calcif Tissue Int 37:453–460

    Google Scholar 

  22. Raisz LG, Rodan GA (1990) Cellular basis of bone turnover. In: Avioli LV, Krane SM (eds) Metabolic Bone Diseases and Clinically Related Disorders. WB Saunders Co, Philadelphia, pp 1–41

    Google Scholar 

  23. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 72:248–254

    Google Scholar 

  24. Yamazaki I (1986) Effect of ipriflavone on the response of uterus and thyroid to estrogen. Life Sci 38:757–764

    Google Scholar 

  25. Yamazaki I, Shino A, Tsukuda R (1986) Effect of ipriflavone on osteoporosis induced by ovariectomy in rats. J Bone Miner Metab 3:205–210

    Google Scholar 

  26. Notoya K, Yoshida K, Tsukuda R, Taketomi S, Tsuda M (1993) Increase in bone mass by ipriflavone alone and in combination with vitamin D3 in immobilized rats (abstract). J Bone Miner Res 8:S274

    Google Scholar 

  27. Bianco P, Fisher LW, Young MF, Termine JD, Gehron Robey P (1990) Expression and localization of the two small proteoglycans, biglycan and decorin, in developing human skeletal and nonskeletal tissues. J Histochem Cytochem 38:1549–1563

    Google Scholar 

  28. Rouslahti E (1988) Structure and biology of proteoglycans. Annu Rev Cell Biol 4:229–255

    Google Scholar 

  29. Ibaraki K, Termine JD, Whitson SW, Young MF (1992) Bone matrix mRNA expression in differentiating fetal bovine osteoblasts. J Bone Miner Res 7:743–754

    Google Scholar 

  30. Weinreb M, Shinar D, Rodan GA (1990) Different pattern of alkaline phosphatase, osteopontin, and osteocalcin expression in developing rat bone visualized by in situ hybridization. J Bone Miner Res 5:831–842

    Google Scholar 

  31. Rodan SB, Wesolowski G, Yoon K, Rodan GA (1989) Opposing effects of fibroblast growth factor and pertussis toxin on alkaline phosphatase, osteopontin, osteocalcin, and type I collagen mRNA levels in ROS 17/2.8 cells. J Biol Chem 264:19934–19941

    Google Scholar 

  32. Fisher LW, Hawkins GR, Tuross N, Termine JD (1987) Purification and partial characterization of small proteoglycans I and II, bone sialoproteins I and II and osteonectin from the mineral compartment of developing human bone. J Biol Chem 262:9702–9708

    Google Scholar 

  33. Reinholt FP, Hultenby K, Oldberg A, Heinegard D (1990) Osteopontin—a possible anchor of osteoclasts to bone. Proc Natl Acad Sci USA 87:4473–4475

    Google Scholar 

  34. Davies PA, Oyajobi BO, Oreffo ROC, Johnstone D, Russell RGG (1993) Effects of bone-active agents (parathyroid hormone, oestrogens, ipriflavone, and fluoride) on osteogenesis as assessed by formation of fibroblast colony-forming cells (CFU-F) in human bone marrow cultures (abstract). J Bone Miner Res 8:S245

    Google Scholar 

  35. Yoshida K, Tsukamoto T, Tanayama S, Uemura I, Shibata K (1985) Disposition of ipriflavone (TC-80) in rats and dogs. Radioisotopes 34:618–623

    Google Scholar 

  36. Rondelli I, Acerbi D, Ventura P (1991) Steady-state pharmaco-kinetics of ipriflavone and its metabolites in patients with renal failure. Int J Clin Pharmacol Res 11:183–192

    Google Scholar 

  37. Brandi ML, Gennari C (1993) Ipriflavone: new insights into its mechanisms of action on bone remodeling (Letter). Calcif Tissue Int 52:151–152

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Bone and Mineral Diseases, Washington University School of Medicine, 216 S. Kingshighway blvd., St. Louis, Missouri, USA

    S. -L. Cheng, S. -F. Zhang, T. L. Nelson, P. M. Warlow & R. Civitelli

  2. the Jewish Hospital of St. Louis, 216 S. Kingshighway blvd., St. Louis, Missouri, USA

    S. -L. Cheng, S. -F. Zhang, T. L. Nelson, P. M. Warlow & R. Civitelli

Authors
  1. S. -L. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. -F. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. L. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. M. Warlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Civitelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, S.L., Zhang, S.F., Nelson, T.L. et al. Stimulation of human osteoblast differentiation and function by ipriflavone and its metabolites. Calcif Tissue Int 55, 356–362 (1994). https://doi.org/10.1007/BF00299315

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00299315

Key words

Search

Navigation