Systemically available bone morphogenetic protein two and seven affect bone metabolism



Bone morphogenetic protein (BMP)-2 and -7 are used in patients with long-bone fractures, nonunions and spinal fusions. It is unknown whether their potential systemic bioavailability following local bone administration might affect skeletal metabolism. To answer this question, we examined effects of systemically administered BMP-2 and -7 on bone in a newly developed rat model with a low level of calciotropic hormones.


Removal of thyroid and parathyroid glands (TPTx) in rats resulted in a decreased level of calciotropic hormones and subsequent bone loss assessed by micro computed tomography (micro-CT) and measurement of serum bone formation and resorption markers, including osteocalcin, C-telopeptide, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Results were complemented with in vitro studies on osteoblast and osteoclast activity by both BMP-2 and -7. The doses used were calculated from published pharmacodynamic studies and bioavailability results from preclinical BMP-2 and -7 studies.


TPTx resulted in bone loss, which was restored by systemic administration of 10–70 μg/kg of BMP-2 and 10–250 μg/kg of BMP-7. BMP-2 showed a higher capacity for enhancing trabecular microarchitecture, whereas BMP-7 augmented trabecular thickness. In vitro experiments revealed that BMP-2 and -7 when uncoupled increased the number and activity of both osteoblasts and osteoclasts.


Surprisingly, both BMP-2 and -7 showed an increased bone volume in an in vivo environment of low calciotropic hormones. Locally administered BMP-2 and -7 from bone devices might become partially available in circulation but will not mediate systemic bone loss.

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  1. 1.

    Vukicevic S, Stavljenic A, Pecina M (1995) Discovery and clinical applications of bone morphogenetic proteins. Eur J Clin Chem Clin Biochem 33:661–671

    CAS  PubMed  Google Scholar 

  2. 2.

    Jelic M, Pecina M, Haspl M, Kos J, Taylor K, Maticic D, McCartney J, Yin S, Rueger D, Vukicevic S (2001) Regeneration of articular cartilage chondral defects by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth Factors 19:101–113

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Jelic M, Grgurevic L, Vukicevic S (2014) Scaffold-free endogenous healing of the articular cartilage lesion. In: Doral MN and Karlsson J (eds) Sport injuries: prevention, diagnosis, treatment and rehabilitation, 2nd ed. Springer-Verlag

  4. 4.

    Pecina M, Jelic M, Martinovic S, Haspl M, Vukicevic S (2002) Articular cartilage repair: the role of bone morphogenetic proteins. Int Orthop 26:131–136

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  5. 5.

    Govender S, Csimma C, Genant HK, Valentin-Orpan A, BMP-2 Evaluation in surgery for Tibial Trauma (BESTT) study group et al (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of 450 patients. J Bone Joint Surg Am 84-A:2123–2134

    PubMed  Google Scholar 

  6. 6.

    Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A:151–158

    Google Scholar 

  7. 7.

    Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, Helfand M (2013) Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spinal fusion: a systematic review and meta-analysis. Ann Intern Med 158:890–902

    PubMed  Article  Google Scholar 

  8. 8.

    Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, Stewart LA (2013) Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med 158:877–889

    PubMed  Article  Google Scholar 

  9. 9.

    Ekrol I, Hajducka C, Court-Brown C, McQueen MM (2008) A comparison of rhBMP-7 (OP-1) and autogenous graft for metaphyseal defects after osteotomy of distal radius. Injury 39:S73–S82

    PubMed  Article  Google Scholar 

  10. 10.

    McGee MA, Findlay DM, Howie DW, Carbone A, Ward P, Stamenkov R, Page TT, Bruce WJ, Wildenauer CI, Toth C (2004) The use of OP-1 in femoral impaction grafting in a sheep model. J Orthop Res 22:1008–1015

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Peric M, Dumic-Cule I, Grcevic D, Matijasic M, Verbanac D, Grgurevic L, Trkulja V, Bagi C, Vukicevic S (2014) The rational use of animal models in the evaluation of novel bone regenerative therapies. Bone. doi:10.1016/j.bone.2014.07.010

  12. 12.

    Dumic-Cule I, Draca N, Luetic AT, Jezek D, Rogic D, Grgurevic L, Vukicevic S (2014) TSH prevents bone resorption and with calcitriol synergistically stimulates bone formation in rats with low levels of calciotropic hormones. Horm Metab Res 46:305–312

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression dana using real-time quantitative PCR and the 2(−Delta Delta C(T)). Methods 25:402–408

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Vukicevic S, Oppermann H, Verbanac D, Jankolija M, Popek I, Curak J, Brkljacic J, Pauk M, Erjavec I, Francetic I, Dumic-Cule I, Jelic M, Durdevic D, Vlahovic T, Novak R, Kufner V, Bordukalo Niksic T, Kozlovic M, Banic Tomisic Z, Bubic-Spoljar J, Bastalic I, Vikic-Topic S, Peric M, Pecina M, Grgurevic L (2014) The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing. Int Orthop 38:635–647

    PubMed  Article  Google Scholar 

  16. 16.

    Suzuki J, Otsuka F, Takeda M, Kenichi I, Tomoko M, Mimura Y, Ogura T, Doihara H, Makino H (2005) Functional role of the bone morphogenetic protein system in thyrotropin signaling in porcine thyroid cells. Biochem Biophys Res Commun 327:1124–1130

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Kamiya N, Ye L, Kobayashi T, Lucas DJ, Mochida Y, Yamauchi M, Kronenberg HM, Feng JQ, Mishina Y (2008) Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J Bone Miner Res 23:2007–2017

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. 18.

    Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Sanchez-Fernandez MA, Gallois A, Riedl T, Jurdic P, Hoflack B (2008) Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling. PLoS One 3:e3537

    PubMed Central  PubMed  Article  Google Scholar 

  20. 20.

    Simic P, Culej JB, Orlic I, Grgurevic L, Draca N, Spaventi R, Vukicevic S (2006) Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem 281:25509–25521

    CAS  PubMed  Article  Google Scholar 

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This work was supported in part by the Croatian Science Foundation, project 08/5 BONE6-BIS. We acknowledge Djurdja Car and Mirjana Marija Renic for providing animal care in all rat studies.

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Correspondence to Slobodan Vukicevic.

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Dumic-Cule, I., Brkljacic, J., Rogic, D. et al. Systemically available bone morphogenetic protein two and seven affect bone metabolism. International Orthopaedics (SICOT) 38, 1979–1985 (2014).

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  • Bone morphogenetic protein 2
  • Bone morphogenetic protein 7
  • Micro-CT
  • Bone volume