International Journal of Hematology

, Volume 77, Issue 1, pp 75–81 | Cite as

Effect of Granulocyte Colony-Stimulating Factor on Bone Metabolism During Peripheral Blood Stem Cell Mobilization

  • Tsutomu Watanabe
  • Hiroko Suzuya
  • Toshihiro Onishi
  • Sachiyo Kanai
  • Michiya Kaneko
  • Hiroyoshi Watanabe
  • Ryuji Nakagawa
  • Yoshifumi Kawano
  • Yoichi Takaue
  • Yasuhiro Kuroda
  • James E. Talmadge


Granulocyte colony—stimulating factor (G-CSF) has been shown to affect the biochemical markers of bone metabolism, including serum bone alkaline phosphatase (BALP), serum osteocalcin, and urine deoxypyridinoline. To determine the association between bone resorption and formation and the G-CSF—induced mobilization of peripheral blood stem cells (PBSC), we examined these markers during mobilization in 19 healthy donors. The average (± SEM) serum BALP level before treatment was 81.6 ± 17.0 IU/dL, and the level increased significantly to 117.7 ± 15.8 IU/dL on day 5 of G-CSF administration (P < .0001). The urine deoxypyridinoline level before treatment was 12.3 ± 2.4 nmol/mmol creatinine, and this level also increased significantly to 19.4 ± 3.0 nmol/mmol creatinine on day 5 of G-CSF administration (P < .0001). In contrast, the average level of serum osteocalcin significantly decreased from 8.07 ± 2.88 ng/mL to 1.53 ± 0.18 ng/mL on day 5 (P = .0353). During G-CSF administration, we also studied the serum levels of various cytokines (IL-lβ, osteoclastogenesis inhibitory factor [OCIF], IL-6, tumor necrosis factor a, transforming growth factor β, interferon-γ, macrophage colony—stimulating factor) related to bone metabolism. Only the kinetics of OCIF were significantly affected. The serum level of OCIF increased immediately after the start of G-CSF administration and remained high during G-CSF administration. These results demonstrate that high-dose G-CSF affects bone metabolism and that OCIF may play a role in bone metabolism. Consistent with the notion that G-CSF affects bone metabolism, a significant correlation was observed between CD34+ cell yield and the increase in urine deoxypyridinoline but not for the changes in serum BALP and osteocalcin levels. This result suggests that bone resorption is either directly or indirectly related to the mobilization of PBSC by G-CSF.

Key words

Peripheral blood stem cells Mobilization G-CSF Bone metabolism 


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  1. 1.
    To LB, Haylock DN, Simmons PJ, Juttner CA. The biology and clinical uses of blood stem cells.Blood. 1997;89:2233–2258.PubMedGoogle Scholar
  2. 2.
    Anderlini P, Przepiorka D, Champlin R, Körbling M. Biologic and clinical effects of granulocyte colony-stimulating factor in normal individuals.Blood. 1996;88:2819–2825.PubMedGoogle Scholar
  3. 3.
    Engelhardt M, Bertz H, Alting M, et al. High-versus standard-dose filgrastim (rhG-CSF) for mobilization of peripheral-blood progenitor cells from allogeneic donors and CD34+ immunoselection.J Clin Oncol. 1999;17:2160–2172.PubMedGoogle Scholar
  4. 4.
    de la Rubin J, Martínez C, Solano C, et al. Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Spanish Group of Allo-PBT.Bone Marrow Transplant. 1999;24:723–728.CrossRefGoogle Scholar
  5. 5.
    Snowden JA, Biggs JC, Milliken ST, et al. A randomized, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for hematopoietic stem cell mobilization in patients with severe active rheumatoid arthritis.Bone Marrow Transplant. 1998;22:1035–1041.PubMedCrossRefGoogle Scholar
  6. 6.
    Bishop NJ, Williams DM, Compston JC, et al. Osteoporosis in severe congenital neutropenia treated with granulocyte colony-stimulating factor.Br J Haematol. 1995;89:927–928.PubMedCrossRefGoogle Scholar
  7. 7.
    Takahashi T, Wada T, Mori M, et al. Overexpression of the granulocyte colony-stimulating factor gene leads to osteoporosis in mice.Lab Invest. 1996;74:827–834.PubMedGoogle Scholar
  8. 8.
    Lee MY, Fukunaga R, Lee TJ, et al. Bone modulation in sustained hematopoietic stimulation in mice.Blood. 1991;77:2135–2141.PubMedGoogle Scholar
  9. 9.
    Papayannopoulou T, Nakamoto B. Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin.Proc Natl Acad Sci USA. 1993;90:9374–9378.PubMedCrossRefGoogle Scholar
  10. 10.
    Lévesque JP, Leavesley DI, Niutta S, et al. Cytokines increase human hematopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins.J Exp Med. 1995;181:1805–1815.PubMedCrossRefGoogle Scholar
  11. 11.
    Voermans C, Gerritsen WR, dem Borne AE, van der Schoot CE. Increased migration of cord blood-derived CD34+ cells as compared to bone marrow and mobilized peripheral blood CD34+ cells across uncoated or fibronectin-coated filters.Exp Hematol. 1999;27:1806–1814.PubMedCrossRefGoogle Scholar
  12. 12.
    Petit I, Szyper-Kravitz M, Naglar A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4.Nat Immunol. 2002;3:687–694.PubMedCrossRefGoogle Scholar
  13. 13.
    Möhle R, Murea S, Kirsch M, Hass R. Differential expression of L-selectin, VLA-4, and LFA-1 on CD34+ progenitor cells from bone marrow and peripheral blood during G-CSF-enhanced recovery.Exp Hematol. 1995;23:1535–1542.PubMedGoogle Scholar
  14. 14.
    Watanabe T, Kawano Y, Kanamaru S, et al. Endogenous interleukin-8 (IL-8) surge in granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization.Blood. 1999;93:1157–1163.PubMedGoogle Scholar
  15. 15.
    Roodman GD. Cell biology of the osteoclast.Exp Hematol. 1999;27:1229–1241.PubMedCrossRefGoogle Scholar
  16. 16.
    Jimi E, Shuto T, Koga T. Macrophage colony-stimulating factor and interleukin-1 alpha maintain the survival of osteoclast-like cells.Endocrinology. 1995;136:808–811.PubMedCrossRefGoogle Scholar
  17. 17.
    Fuller K, Owens JM, Jagger CJ, et al. Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts.J Exp Med. 1993;178:1733–1744.PubMedCrossRefGoogle Scholar
  18. 18.
    Pfeilschifter J, Chenu C, Bird A, et al. Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclast-like cells in vitro.J Bone Miner Res. 1989;4:113–118.PubMedGoogle Scholar
  19. 19.
    Murray RE, McGuigan F, Grant SF, et al. Polymorphisms of the interleukin-6 gene are associated with bone mineral density.Bone. 1997;21:89–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhou H, Choong PC, Chou ST, et al. Transforming growth factor beta 1 stimulates bone formation and resorption in an in-vitro model in rabbits.Bone. 1995;17:443S-448S.PubMedCrossRefGoogle Scholar
  21. 21.
    Fujita T, Mastui T, Nakao Y, et al. Cytokines and osteoporosis.Ann N Y Acad Sci. 1990;587:371–375.PubMedGoogle Scholar
  22. 22.
    Yasuda H, Shima N, Nakagawa N, et al. Identify of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro.Endocrinology. 1998;139:1329–1337.PubMedCrossRefGoogle Scholar
  23. 23.
    Delmas PD. Biochemical markers of bone turnover.J Bone Miner Res. 1993;8(suppl 2): S549-S555.PubMedCrossRefGoogle Scholar
  24. 24.
    Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9-mediated release of kit-ligand.Cell. 2002;109:625–637.PubMedCrossRefGoogle Scholar
  25. 25.
    Janowska-Wieczorek A, Marquez LA, Dobrowsky A, Ratajczak MZ, Cabuhat ML. Differential MMP and TIMP production by human marrow and peripheral blood CD34+ cells in response to chemokines.Exp Hematol. 2000;28:1274–1285.PubMedCrossRefGoogle Scholar
  26. 26.
    Lévesque JP, Takamatsu Y, Nilsson S, Haylock DN, Simmons PJ. Vascular cell adhesion molecule-1 (CD106) is cleaved by neu- trophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor.Blood. 2001;98:1289–1297.PubMedCrossRefGoogle Scholar
  27. 27.
    Bonilla MA, Dale D, Zeidler C, et al. Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias.Br J Haematol. 1994;88:723–730.PubMedCrossRefGoogle Scholar
  28. 28.
    Soshi S, Takahashi HE, Tanizawa T, et al. Effects of recombinant human granulocyte colony-stimulating factor (rh G-CSF) on rat bone: inhibition of bone formation at the endosteal surface of vertebra and tibia.Calcif Tissue Int. 1996;58:337–340.PubMedGoogle Scholar
  29. 29.
    Morris HA, Chatterton BE, Ross PD, Durbridge TC. Diagnostic procedures. In: Need AG, Morris HA, eds.Metabolic Bone and Stone Disease. Edinburgh, UK: Churchill Livingstone; 1993:339–379.Google Scholar
  30. 30.
    Takamatsu Y, Simmons PJ, Moore RJ, et al. Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization.Blood. 1998;92:3465–3473.PubMedGoogle Scholar
  31. 31.
    Shinar DM, Sato M, Rodan GA. The effect of hematopoietic growth factors on the generation of osteoclast-like cells in mouse bone marrow cultures.Endocrinology. 1990;126:1728–1735.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  • Tsutomu Watanabe
    • 1
  • Hiroko Suzuya
    • 1
  • Toshihiro Onishi
    • 1
  • Sachiyo Kanai
    • 1
  • Michiya Kaneko
    • 1
  • Hiroyoshi Watanabe
    • 1
  • Ryuji Nakagawa
    • 1
  • Yoshifumi Kawano
    • 2
  • Yoichi Takaue
    • 3
  • Yasuhiro Kuroda
    • 1
  • James E. Talmadge
    • 4
  1. 1.Department of PediatricsUniversity ofTokushima School of MedicineTokushimaJapan
  2. 2.Department of PediatricsKyushu Cancer CenterFukuoka
  3. 3.Department of Internal MedicineNational Cancer CenterTokyoJapan
  4. 4.Department of Pathology/MicrobiologyUniversity of Nebraska Medical CenterOmahaUSA

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