HSS Journal

, Volume 3, Issue 2, pp 169–172 | Cite as

Alendronate Inhibits PTH (1–34)-induced Bone Morphogenetic Protein Expression in MC3T3-E1 Preosteoblastic Cells

  • Paul S. Issack
  • Margaret H. Lauerman
  • David L. Helfet
  • Stephen B. Doty
  • Joseph M. Lane
Original Article

Abstract

The bisphosphonate class of antiresorptive drugs and active forms of parathyroid hormone (PTH (1–34)) have been used clinically to enhance bone mass and density in patients with osteoporosis. Abundant evidence suggests that the mechanism by which PTH (1–34) increases bone density is stimulation of osteoblast differentiation. Although bisphosphonates have been classically thought to increase bone density by inhibiting osteoclasts, there is increasing evidence to suggest that bisphosphonates have direct stimulatory effects on osteoblast differentiation. Interestingly, in patients with osteoporosis, combination therapy with bisphosphonates and PTH (1–34) is not synergistic in increasing bone density; bisphosphonates appear to blunt the effect of PTH (1–34). To begin to understand the mechanism governing the effects of these agents on osteoblasts and a possible explanation for their apparent antagonism, we examined the expression of several bone morphogenetic proteins (BMPs) in MC3T3-E1 preosteoblastic cells either untreated, or treated with alendronate, parathyroid hormone, or a combination of the two agents. We find by reverse transcriptase-polymerase chain reaction (RT-PCR) that while alendronate fails to induce the expression of any of the BMPs tested, several BMPs are induced by PTH (1–34). The induction of the PTH (1–34)-inducible BMPs is blocked with simultaneous alendronate treatment. These data suggest that alendronate interferes with PTH (1–34)-induced BMP gene transcription and provides a possible basis for the antagonism observed between the two agents in increasing bone density.

Key words

osteoblasts bisphosphonates parathyroid hormone BMPs 

References

  1. 1.
    Lin JT, Lane JM (2003) Bisphosphonates. J Am Acad Orthop Surg 11:1–4PubMedGoogle Scholar
  2. 2.
    Madore GR, Sherman PJ, Lane JM (2004) Parathyroid hormone. J Am Acad Orthop Surg 12:67–71PubMedGoogle Scholar
  3. 3.
    Bukowski JF, Dascher CC, Das H (2005) Alternative bisphosphonate targets and mechanisms of action. Biochem Biophys Res Commun 328:746–750PubMedCrossRefGoogle Scholar
  4. 4.
    Giuliani N, Pedrazzoni M, Negri G et al (1998) Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone 22:455–461PubMedCrossRefGoogle Scholar
  5. 5.
    Abe Y, Kawakami A, Nakashima T et al (2000) Etidronate inhibits human osteoblast apoptosis by inhibition of pro-apoptotic factor(s) produced by activated T cells. J Lab Clin Med 136:344–354PubMedCrossRefGoogle Scholar
  6. 6.
    Plotkin LI, Weinstein RS, Parfitt AM et al (1999) Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104:1363–1374PubMedCrossRefGoogle Scholar
  7. 7.
    von Knoch F, Jaquiery C, Kowalsky M et al (2005) Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells. Biomaterials 26:6941–6949CrossRefGoogle Scholar
  8. 8.
    Black DM, Greenspan SL, Ensrud KE et al (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349:1207–1215PubMedCrossRefGoogle Scholar
  9. 9.
    Finkelstein JS, Hayes A, Hunzelman JL et al (2003) The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349:1216–1226PubMedCrossRefGoogle Scholar
  10. 10.
    Lecart MP, Bruyere O, Reginster JY (2004) Combination/sequential therapy in osteoporosis. Curr Osteoporos Rep 2:123–130PubMedCrossRefGoogle Scholar
  11. 11.
    Reddi AH (2001) Bone morphogenetic proteins: from basic science to clinical applications. J Bone Jt Surg Am 83-A(Suppl 1):S1–S6Google Scholar
  12. 12.
    Gopalakrishnan R, Jiang D, Reith E et al (2002) Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells. J Bone Miner Res 17:101–110PubMedCrossRefGoogle Scholar
  13. 13.
    Noda M, Rodan GA (1986) Type-beta transforming growth factor inhibits proliferation and expression of alkaline phosphatase in murine osteoblast-like cells. Biochem Biophys Res Commun 140:56–65PubMedCrossRefGoogle Scholar
  14. 14.
    Noda M, Vogel R (1989) Fibroblast growth factor enhances type beta 1 transforming growth factor gene expression in osteoblast-like cells. J Cell Biol 109:2529–2535PubMedCrossRefGoogle Scholar
  15. 15.
    Tsuji K, Ito Y, Noda M (1998) Expression of the PEBP2alphaA/AML3/CBFA1 gene is regulated by BMP4/7 heterodimer and its overexpression suppresses type I collagen and osteocalcin gene expression in osteoblastic and nonosteoblastic mesenchymal cells. Bone 22:87–92PubMedCrossRefGoogle Scholar
  16. 16.
    Xiao G, Cui Y, Ducy P et al (1997) Ascorbic acid-dependent activation of the osteocalcin promoter in MC3T3-E1 preosteoblasts: requirement for collagen matrix synthesis and the presence of an intact OSE2 sequence. Mol Endocrinol 11:1103–1113PubMedCrossRefGoogle Scholar
  17. 17.
    Xiao G, Jiang D, Gopalakrishnan R et al (2002) Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J Biol Chem 277:36181–36187PubMedCrossRefGoogle Scholar
  18. 18.
    Im GI, Qureshi SA, Kenney J et al (2004) Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 25:4105–4115PubMedCrossRefGoogle Scholar
  19. 19.
    Jiang D, Franceschi RT, Boules H et al (2004) Parathyroid hormone induction of the osteocalcin gene. Requirement for an osteoblast-specific element 1 sequence in the promoter and involvement of multiple-signaling pathways. J Biol Chem 279:5329–5337PubMedCrossRefGoogle Scholar
  20. 20.
    Issack PS, DiCesare PE (2003) Recent advances toward the clinical application of bone morphogenetic proteins in bone and cartilage repair. Am J Orthop 32:429–436PubMedGoogle Scholar
  21. 21.
    Wozney JM, Rosen V (1998) Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop Relat Res 346:26–37PubMedCrossRefGoogle Scholar
  22. 22.
    Ge G, Greenspan DS (2006) Developmental roles of the BMP1/TLD metalloproteinases. Birth Defects Res C Embryo Today 78:47–68PubMedCrossRefGoogle Scholar
  23. 23.
    Ge G, Greenspan DS (2006) BMP1 controls TGFbeta1 activation via cleavage of latent TGF beta-binding protein. J Cell Biol 175:111–120PubMedCrossRefGoogle Scholar
  24. 24.
    Jasuja R, Ge G, Voss NG et al (2007) Bone morphogenetic protein 1 prodomain specifically binds and regulates signaling by none morphogenetic proteins 2 and 4. J Biol Chem 282:9053–9062PubMedCrossRefGoogle Scholar
  25. 25.
    Einhorn TA, Majeska RJ, Mohaideen A et al (2003) A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Jt Surg Am 85-A(Suppl):1425–1435Google Scholar
  26. 26.
    Friedlaender GE, Perry CR, Cole JD et al (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Jt Surg Am 83-A(Suppl):S151–S158Google Scholar
  27. 27.
    Govender S, Csimma C, Genant HK et al (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Jt Surg Am 84-A:2123–2134Google Scholar

Copyright information

© Hospital for Special Surgery 2007

Authors and Affiliations

  • Paul S. Issack
    • 1
  • Margaret H. Lauerman
    • 1
  • David L. Helfet
    • 1
  • Stephen B. Doty
    • 1
  • Joseph M. Lane
    • 1
  1. 1.Hospital for Special SurgeryNew YorkUSA

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