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Erschienen in: Clinical Oral Investigations 5/2018

02.12.2017 | Original Article

Prolonged use of alendronate alters the biology of cranial repair in estrogen-deficient rats’ associated simultaneous immunohistochemical expression of TGF-β1+, α-ER+, and BMPR1B-

verfasst von: Allan Fernando Giovanini, Giuliene Nunes de Sousa Passoni, Isabella Göhringer, Tatiana Miranda Deliberador, João Cesar Zielak, Carmem Lucia Muller Storrer, Thais Andrade Costa - Casagrande, Rafaela Scariot

Erschienen in: Clinical Oral Investigations | Ausgabe 5/2018

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Abstract

Objectives

TGF-β1 is a cytokine that may induce both osteoneogenesis through Runx-2 or fibrosis via the transcription of α-smooth muscle actin (α-SMA). Because it has been previously known that alendronate increases the level of TGF-β1 and that under the usual condition of bone metabolism the estrogen may prevent the fibrotic effect of TGF-β1, the aim of this study was to evaluate if alendronate alters the cellular differentiation process post calvarial surgery in estrogen-deficient specimens.

Materials and methods

A transosseous defect that was 5 mm in diameter was created on the calvarium of each of 32 female rats with previous ovarian-salpingo-oophorectomy. All defects were treated with autografts, and 16 rats received the administration of 1 mg/kg of alendronate three times a week until euthanasia on the 15th and 60th day post surgery. Histomorphometric and immunohistochemical analyses of the expression of TGF-β1, estrogen receptor alpha nuclear (α-ER), α-SMA, BMPR1B, and Runx-2 were performed, and ELISA was used to measure the level of estrogen.

Results

All animals demonstrated low levels of estrogen post ovarian-salpingo-oophorectomy. The histological results demonstrated larger bone matrix deposition in specimens treated with alendronate on the 15th day post surgery. The result was associated with a higher co-expression of TGF-β1, BMPR1B, and Runx-2 when compared with the control group. In addition, on the 60th day post surgery, the increase of bone matrix deposition from 15th to 60th day was discrete in specimens treated with alendronate compared with the control group. This result coincided with the intense simultaneous expression of TGF-β1, α-ER, and α-SMA, whereas the expression of BMPR1B and Runx-2 decreased.

Conclusion

The prolonged administration of alendronate altered the cranial repair in ovarian-salpingo-oophorectomized specimens due to the simultaneous occurrence of low estrogen and the presence of TGF-β1+/α-ER+ inducing the presence of α-SMA+, whereas BMPR1B and Runx-2 were suppressed.

Clinical relevance

The prolonged administration of alendronate alters osteoneogenesis and induces an unusual microenvironment in the bone that seems to imitate the physiological tissue damage that culminates in the loss of the functional layer of endometrium.
Literatur
1.
Zurück zum Zitat Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S (2007) Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130(5):811–823. https://doi.org/10.1016/j.cell.2007.07.025 CrossRefPubMed Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S (2007) Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130(5):811–823. https://​doi.​org/​10.​1016/​j.​cell.​2007.​07.​025 CrossRefPubMed
9.
Zurück zum Zitat Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, Coyle D, Tugwell P (2008) Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 23:CD001155 Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, Coyle D, Tugwell P (2008) Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 23:CD001155
11.
Zurück zum Zitat Roelofs AJ, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12(20 Pt 2):6222s–6230sCrossRefPubMed Roelofs AJ, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12(20 Pt 2):6222s–6230sCrossRefPubMed
12.
Zurück zum Zitat Madrid C, Sanz M (2009) What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review. Clin Oral Implants Res 4:87–95CrossRef Madrid C, Sanz M (2009) What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review. Clin Oral Implants Res 4:87–95CrossRef
14.
Zurück zum Zitat Camati PR, Giovanini AF, de Miranda Peixoto HE, Schuanka CM, Giacomel MC, de Araújo MR, Zielak JC, Scariot R, Deliberador TM (2016) Immunoexpression of IGF1, IGF2, and osteopontin in craniofacial bone repair associated with autogenous grafting in rat models treated with alendronate sodium. Clin Oral Investig 21(5):1895–1903. https://doi.org/10.1007/s00784-016-1975-0 CrossRefPubMed Camati PR, Giovanini AF, de Miranda Peixoto HE, Schuanka CM, Giacomel MC, de Araújo MR, Zielak JC, Scariot R, Deliberador TM (2016) Immunoexpression of IGF1, IGF2, and osteopontin in craniofacial bone repair associated with autogenous grafting in rat models treated with alendronate sodium. Clin Oral Investig 21(5):1895–1903. https://​doi.​org/​10.​1007/​s00784-016-1975-0 CrossRefPubMed
20.
Zurück zum Zitat Giovanini AF, Deliberador TM, Tannuri Nemeth JE, Crivellaro VR, Portela GS, de Oliveira Filho MA et al (2013) Leukocyte-platelet-rich plasma (L-PRP) impairs the osteoconductive capacity of the autograft associated to changes in the immunolocalization of TGF-beta1 and its co-expression with Wnt10b and CD34 cells. J Craniomaxillofac Surg 41:180–186CrossRef Giovanini AF, Deliberador TM, Tannuri Nemeth JE, Crivellaro VR, Portela GS, de Oliveira Filho MA et al (2013) Leukocyte-platelet-rich plasma (L-PRP) impairs the osteoconductive capacity of the autograft associated to changes in the immunolocalization of TGF-beta1 and its co-expression with Wnt10b and CD34 cells. J Craniomaxillofac Surg 41:180–186CrossRef
21.
Zurück zum Zitat Giovanini AF, Gonzaga CC, Zielak JC, Deliberador TM, Kuczera J, Goringher I et al (2010) Platelet-rich plasma (PRP) impairs the craniofacial bone repair associated with its elevated TGF-beta levels and modulates the co-expression between collagen III and alpha-smooth muscle actin. J Orthop Res 29(3):457–463. https://doi.org/10.1002/jor.21263 CrossRefPubMed Giovanini AF, Gonzaga CC, Zielak JC, Deliberador TM, Kuczera J, Goringher I et al (2010) Platelet-rich plasma (PRP) impairs the craniofacial bone repair associated with its elevated TGF-beta levels and modulates the co-expression between collagen III and alpha-smooth muscle actin. J Orthop Res 29(3):457–463. https://​doi.​org/​10.​1002/​jor.​21263 CrossRefPubMed
28.
Zurück zum Zitat Giovanini AF, Grossi JR, Gonzaga CC, Zielak JC, Gohringer I, Vieira Jde S et al (2014) Leukocyte-platelet-rich plasma (L-PRP) induces an abnormal histophenotype in craniofacial bone repair associated with changes in the immunopositivity of the hematopoietic clusters of differentiation, osteoproteins, and TGF-beta1. Clin Implant Dent Relat Res 16(2):259–272. https://doi.org/10.1111/j.1708-8208.2012.00478.x CrossRefPubMed Giovanini AF, Grossi JR, Gonzaga CC, Zielak JC, Gohringer I, Vieira Jde S et al (2014) Leukocyte-platelet-rich plasma (L-PRP) induces an abnormal histophenotype in craniofacial bone repair associated with changes in the immunopositivity of the hematopoietic clusters of differentiation, osteoproteins, and TGF-beta1. Clin Implant Dent Relat Res 16(2):259–272. https://​doi.​org/​10.​1111/​j.​1708-8208.​2012.​00478.​x CrossRefPubMed
32.
Zurück zum Zitat Evans GS, Gibson DF, Roberts SA, Hind TM, Potten CS (1990) Proliferative changes in the genital tissue of female mice during the oestrous cycle. Cell Tissue Kinet 23(6):619–635PubMed Evans GS, Gibson DF, Roberts SA, Hind TM, Potten CS (1990) Proliferative changes in the genital tissue of female mice during the oestrous cycle. Cell Tissue Kinet 23(6):619–635PubMed
34.
Zurück zum Zitat Nishikawa Y, Ikegami H, Sakata M, Mizutani T, Morishige K, Kurachi H, Hirota K, Miyake A, Tanizawa O (1993) Ovariectomy increases the level of estrogen receptor mRNA and estrogen receptor binding sites in female rat adipose tissue. J Endocrinol Investig 16(8):579–583. https://doi.org/10.1007/BF03347674 CrossRef Nishikawa Y, Ikegami H, Sakata M, Mizutani T, Morishige K, Kurachi H, Hirota K, Miyake A, Tanizawa O (1993) Ovariectomy increases the level of estrogen receptor mRNA and estrogen receptor binding sites in female rat adipose tissue. J Endocrinol Investig 16(8):579–583. https://​doi.​org/​10.​1007/​BF03347674 CrossRef
40.
Zurück zum Zitat Tsoumpra MK, Muniz JR, Barnett BL, Kwaasi AA, Pilka ES, Kavanagh KL, Evdokimov A, Walter RL, von Delft F, Ebetino FH, Oppermann U, Russell RGG, Dunford JE (2015) The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants. Bone 81:478–486. https://doi.org/10.1016/j.bone.2015.08.020 CrossRefPubMedPubMedCentral Tsoumpra MK, Muniz JR, Barnett BL, Kwaasi AA, Pilka ES, Kavanagh KL, Evdokimov A, Walter RL, von Delft F, Ebetino FH, Oppermann U, Russell RGG, Dunford JE (2015) The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants. Bone 81:478–486. https://​doi.​org/​10.​1016/​j.​bone.​2015.​08.​020 CrossRefPubMedPubMedCentral
45.
Zurück zum Zitat Dinh A, Sriprasert I, Williams AR, Archer DF A review of the endometrial histologic effects of progestins and progesterone receptor modulators in reproductive age women. Contraception 91:360–367 Dinh A, Sriprasert I, Williams AR, Archer DF A review of the endometrial histologic effects of progestins and progesterone receptor modulators in reproductive age women. Contraception 91:360–367
46.
Zurück zum Zitat Chegini N, Zhao Y, Williams RS, Flanders KC (1994) Human uterine tissue throughout the menstrual cycle expresses transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, TGF beta 3, and TGF beta type II receptor messenger ribonucleic acid and protein and contains [125I]TGF beta 1-binding sites. Endocrinology 135(1):439–449. https://doi.org/10.1210/endo.135.1.8013382 CrossRefPubMed Chegini N, Zhao Y, Williams RS, Flanders KC (1994) Human uterine tissue throughout the menstrual cycle expresses transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, TGF beta 3, and TGF beta type II receptor messenger ribonucleic acid and protein and contains [125I]TGF beta 1-binding sites. Endocrinology 135(1):439–449. https://​doi.​org/​10.​1210/​endo.​135.​1.​8013382 CrossRefPubMed
47.
Zurück zum Zitat Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M et al (2007) Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 293:1147–1154CrossRef Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M et al (2007) Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 293:1147–1154CrossRef
48.
Zurück zum Zitat Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47:1394–1400CrossRefPubMed Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47:1394–1400CrossRefPubMed
Metadaten
Titel
Prolonged use of alendronate alters the biology of cranial repair in estrogen-deficient rats’ associated simultaneous immunohistochemical expression of TGF-β1+, α-ER+, and BMPR1B-
verfasst von
Allan Fernando Giovanini
Giuliene Nunes de Sousa Passoni
Isabella Göhringer
Tatiana Miranda Deliberador
João Cesar Zielak
Carmem Lucia Muller Storrer
Thais Andrade Costa - Casagrande
Rafaela Scariot
Publikationsdatum
02.12.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
Clinical Oral Investigations / Ausgabe 5/2018
Print ISSN: 1432-6981
Elektronische ISSN: 1436-3771
DOI
https://doi.org/10.1007/s00784-017-2292-y

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