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

• Published in: Clinical oral investigations Vol. 22; no. 5; pp. 1959 - 1971
• Main Authors: Giovanini, Allan Fernando, de Sousa Passoni, Giuliene Nunes, Göhringer, Isabella, Deliberador, Tatiana Miranda, Zielak, João Cesar, Storrer, Carmem Lucia Muller, Costa - Casagrande, Thais Andrade, Scariot, Rafaela
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2018; Springer Nature B.V
• Subjects: Actin; Actins - metabolism; Alendronate - pharmacology; Alendronic acid; Animals; Autografts; Bisphosphonates; Bone matrix; Bone Morphogenetic Protein Receptors, Type I - metabolism; Bone surgery; Bone turnover; Cell Differentiation - drug effects; Core Binding Factor Alpha 1 Subunit - metabolism; Dentistry; Endometrium; Enzyme-Linked Immunosorbent Assay; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Fibrosis; Immunohistochemistry; Medicine; Original Article; Ovariectomy; Rats; Rats, Wistar; Rodents; Skull; Skull - cytology; Skull - surgery; Smooth muscle; Surgery; Transcription; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Wound Healing - drug effects; Alendronate; Transforming growth factor- TGF-β1; Estrogen receptor, α-smooth muscle actin, bone regeneration
• ISSN: 1432-6981; 1436-3771
• DOI: 10.1007/s00784-017-2292-y

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.