Skip to main content

Role of vascular endothelial growth factor expression in pathogenesis of postmenopausal osteoporosis

Abstract

Background

Vascular endothelial growth factor (VEGF), an angiogenic growth factor, has been proved to play a significant role in bone remodeling. It may be involved in the molecular pathogenesis of postmenopausal osteoporosis.

Aim

The aim of this study was to investigate the expression of VEGF in bone biopsies of postmenopausal osteoporotic patients, assess the relation between the expression of VEGF and bone mineral density (BMD), and to evaluate the association between VEGF, serum estradiol, and bone estrogen receptor-α.

Patients and methods

This study was carried out on 30 female patients who were further subdivided into three groups: premenopausal, perimenopausal, and postmenopausal. All of them were subjected to full assessment of history, thorough clinical examination, and routine laboratory investigations. Serum estradiol levels were measured using ELISA. BMD was detected using DEXA. Bone biopsies were taken and three sections were obtained from each specimen. One was stained with hematoxylin and eosin stain for bone histomorphometrical assessment. The other two sections were stained immunohistochemically for the detection of VEGF and estrogen receptor-α (ER-α) expression.

Results

A highly statistically significant difference was found in VEGF expression between the premenopausal, perimenopausal, and postmenopausal women and also between osteoporotic and nonosteoporotic women. A highly statistically positive correlation was found between VEGF and each of the following: BMD, bone anabolic histomorphometrical parameters E2, and ER-α. However, a highly statistically negative correlation was observed between VEGF and bone histomorphometrical resorption parameters.

Conclusion

VEGF expression is decreased in bone of postmenopausal osteoporotic patients and is correlated to BMD. Its release is dependent on E2 and mediated through ER-α. These suggest that bone alterations induced by reduced estrogen in postmenopausal osteoporosis may be partly through decreased VEGF release. This makes it one of the possible targets in the treatment of postmenopausal osteoporosis.

References

  1. Lane N In: Firestein GS, Budd RC, Harris ED, Mclnnes IB, Ruddy S, Sergent JS (eds). , Metabolic bone disease. Kelley’s Textbook of Rheumatology 8th ed. 2009; Philadelphia, PA: Elsevier; 1579–1599.

  2. Boonen S, Ferrari S, Miller PD, Erikson EF, Sambrook PN, Compston J, et al. Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk — a perspective. J Bone Miner Res 2012; 27:963–974.

    CAS  Article  Google Scholar 

  3. Araldi E, Schipani E Hypoxia, HIFs and bone development. Bone 2010; 47:190–196.

    CAS  Article  Google Scholar 

  4. Tammela T, Enholm B, Alitalo K, Paavonen K The biology of vascular endothelial growth factors. Cardiovasc Res 2005; 65:550–563.

    CAS  Article  Google Scholar 

  5. Bluteau G, Julien M, Magne D, Mallein-Gerin F, Weiss P, Daculsi G, Guicheux J VEGF and VEGF receptors are differentially expressed in chondrocytes. Bone 2007; 40:568–576.

    CAS  Article  Google Scholar 

  6. Pufe T, Claassen H, Scholz-Ahrens KE, Varoga D, Drescher W, Franke AT, et al. Influence of estradiol on vascular endothelial growth factor expression in bone: A study in Gottingen miniature pigs and human osteoblasts. Calcif Tissue Int 2007; 80:184–191.

    CAS  Article  Google Scholar 

  7. Keramaris NC, Calori GM, Nikolaou VS, Schemitsch EH, Giannoudis PV Fracture vascularity and bone healing: A systematic review of the role of VEGF. Injury 2008; 39(Suppl 2):S45–S57.

  8. Street J, Lenehan B Vascular endothelial growth factor regulates osteoblast survival — evidence for an autocrine feedback mechanism. J Orthop Surg Res 2009; 4:1–13.

    Article  Google Scholar 

  9. Yen ML, Su JL, Chien CL, Tseng KW, Yang CY, Chen WF, et al. Diosgenin induces hypoxia–inducible factor–1 activation and angiogenesis through estrogen receptor–related phosphatidylinositol 3–kinase/Akt and p38 mitogen–activated protein kinase pathways in osteoblasts. Mol Pharmacol 2005;68:1061–1073.

    CAS  Article  Google Scholar 

  10. Cebi H, Aksahin E, Yuksel HY, Celebi L, Aktekin CM, Hapa O, et al. Plasma vascular endothelial growth factor levels are similar in subjects with and without osteoporosis. Joint Dis Relat Surg 2010; 21:91–97.

    Google Scholar 

  11. Pufe T, Scholz–Ahrens KE, Franke AT, Petersen W, Mentlein R, Varoga D, et al. The role of vascular endothelial growth factor in glucocorticoid-induced bone loss: Evaluation in a minipig model. Bone 2003; 33:869–876.

    CAS  Article  Google Scholar 

  12. Giannoudis P, Tzioupis C, Almalki T, Buckley R Fracture healing in osteoporotic fractures: Is it really different? A basic science perspective. Injury 2007; 38(Suppl 1):S90–S99.

  13. Schmidt PJ, Rubinow DR Sex hormones and mood in the perimenopause. Ann N Y Acad Sci 2009; 1179:70–85.

    CAS  Article  Google Scholar 

  14. Jagtap VR, Ganu JV, Nagane NS BMD and serum intact osteocalcin in postmenopausal osteoporosis women. Ind J Clin Biochem 2011; 26:70–73.

    CAS  Article  Google Scholar 

  15. Martin–Millan M, Almeida M, Ambrogini E, Han L, Zhao H, Weinstein RS, et al. The estrogen receptor–α in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol 2010;24:323–334.

    CAS  Article  Google Scholar 

  16. Maes C, Carmeliet G In: Ruhrberg C (ed.) Vascular and nonvascular roles of VEGF in bone development. VEGF in development Austin: Springer; 2008; 79–90.

  17. Maes C, Goossens S, Bartunkova S, Drogat B, Coenegrachts L, Stockmans I, et al. Increased skeletal VEGF enhances β-catenin activity and results in excessively ossified bones. EMBO J 2010; 29:424–441.

    CAS  Article  Google Scholar 

  18. Cao JJ Effects of obesity on bone metabolism. J Orthop Surg Res 2011;6:1–7.

    Article  Google Scholar 

  19. Nordin BEC, Need AG, Morris HA, O’Loughlin PD, Horowitz M Effect of age on calcium absorption in postmenopausal women. Am J Clin Nutr 2004;80:998–1002.

    CAS  Article  Google Scholar 

  20. Simon LS Osteoporosis. Clin Geriatr Med 2005; 21:603–629.

    Article  Google Scholar 

  21. Khaled HF, Omar SM Tumor necrosis factor alpha expression in iliac bone biopsy and relation to bone histomorphometry in premenopausal and postmenopausal women. Egypt Rheumatol Rehabil 2008; 35:377–392.

    Google Scholar 

  22. Gruber CJ, Tschugguel W, Schneeberger C, Huber JC Production and actions of estrogens. N Engl J Med 2002; 346:340–352.

    CAS  Article  Google Scholar 

  23. Grady D Management of menopausal symptoms. N Engl J Med 2006; 355:2338–2347.

    CAS  Article  Google Scholar 

  24. HassabβElnaby MM, El-Ganzouri AM, Abdel-Moneeim HF, Moussa MH, Abaza NM Osteoprotegerin (OPG) and histomorphometric assessment in human bone in relation to menopausal status 2007; 85–113.

  25. Jergas M In: Grampp S (ed.) Radiology of osteoporosis. Medical radiology: Diagnostic imaging 2nd ed. Heidelberg: Springer; 2008; 77–104.

  26. Li S, He H, Ding M, He C The correlation of osteoporosis to clinical features: A study of 4382 female cases of a hospital cohort with musculoskeletal symptoms in southwest China. BMC Musculoskeletal Disorders 2010; 11:1–9.

    CAS  Article  Google Scholar 

  27. Estok PJ, Sedlak CA, Doheny MO, Hall R Structural model for osteoporosis preventing behavior in postmenopausal women. Nurs Res 2007;56:148–158.

    Article  Google Scholar 

  28. Zhao Q, Shen X, Zhang W, Zhu G, Qi J, Deng L Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss. Bone 2012; 50:763–770.

    CAS  Article  Google Scholar 

  29. Ding WG, Wei ZX, Liu JB Reduced local blood supply to the tibial metaphysis is associated with ovariectomy–induced osteoporosis in mice. Connect Tissue Res 2011; 52:25–29.

    Article  Google Scholar 

  30. Costa N, Paramanathan S, Mac Donald D, Wierzbicki AS, Hampson G Factors regulating circulating vascular endothelial growth factor (VEGF): Association with bone mineral density (BMD) in post–menopausal osteoporosis. Cytokine 2009; 46:376–381.

    CAS  Article  Google Scholar 

  31. Hiltunen MO, Ruuskanen M, Huuskonen J, Mahanen AJ, Ahonen M, Rutanen J, et al. Adenovirus–mediated VEGF-A gene transfer induces bone formation in vivo. FASEB J 2003; 17:1147–1149.

    CAS  Article  Google Scholar 

  32. Athanasopoulos AN, Schneider D, Keiper T, Alt V, Pendurthi UR, Liegibel UM, et al. Vascular endothelial growth factor (VEGF)-induced upregulation of CCN1 in osteoblasts mediates proangiogenic activities in endothelial cells and promotes fracture healing. J Biol Chem 2007; 282:26746–26753.

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eman A. Kaddah MD.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Cite this article

Nasser, M.E., Khaled, H.F., Kaddah, E.A. et al. Role of vascular endothelial growth factor expression in pathogenesis of postmenopausal osteoporosis. Egypt Rheumatol Rehabil 40, 211–223 (2013). https://doi.org/10.4103/1110-161X.123809

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.4103/1110-161X.123809

Keywords

  • bone mineral density
  • postmenopausal osteoporosis
  • vascular endothelial growth factor