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Published in: Clinical Oral Investigations 3/2020

01-03-2020 | Metoprolol | Original Article

The effects of intraperitoneal metoprolol administration on healing of bone defects in rat tibia: a pilot study

Authors: R. Al Alawy, H. Hammad, R. AlHabashneh

Published in: Clinical Oral Investigations | Issue 3/2020

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Abstract

Objectives

Metoprolol is a cardioselective competitive beta-1 adrenergic receptor antagonist with antihypertensive properties, devoid of intrinsic sympathomimetic activity. Various studies have suggested the effect of beta-blockers on bone remodeling. We aimed to investigate whether metoprolol affects bone remodeling by altering anti-inflammatory and pro-inflammatory cytokines.

Materials and methods

Surgical defects of 3 mm diameter were created in tibiae of 72 Sprague-Dawley rats. Rats were randomly assigned to a control group without metoprolol treatment (n = 36), and a test group treated with 0.1 mg/kg/day metoprolol (n = 36). Six rats from each group were sacrificed at days 0, 1, 3, 5, 7, and 14. The percentages of cells, which showed positive immunohistochemical staining for IL-1β, IL-6, IL-10, and RANKL, were assessed in the defect area. Differences in percentages of stained cells within each of the test and control groups over various time intervals were tested using one-way ANOVA test. A P value of < 0.05 was considered statistically significant.

Results

No significant differences in IL-1β, IL-10, IL-6, and RANKL expressions were found between test and control groups at the same interval. Significant reduction was observed at different time intervals in the same group (P < 0.05).

Conclusion

Metoprolol did not reduce bone-active cytokine: IL-1β, IL-6, and RANKL. It also did not elevate IL-10 expression levels. Thus, it does not appear to decrease osteoclastogenesis.

Clinical relevance

Results from this animal model help us understand any effect of metoprolol on bone healing by potential contribution to different real-world clinical research.
Literature
1.
go back to reference Gerstenfeld L, Cullinane D, Barnes G, Graves D, Einhorn T (2003) Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 88:873–884CrossRef Gerstenfeld L, Cullinane D, Barnes G, Graves D, Einhorn T (2003) Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 88:873–884CrossRef
2.
go back to reference Einhorn T, Majeska RJ, Rush E, Levine P, Horowitz M (1995) The expression of cytokine activity by fracture callus. J Bone Miner Res 10(8):1272–1281CrossRef Einhorn T, Majeska RJ, Rush E, Levine P, Horowitz M (1995) The expression of cytokine activity by fracture callus. J Bone Miner Res 10(8):1272–1281CrossRef
3.
go back to reference Harada SI, Rodan GA (2003) Control of osteoblast function and regulation of bone mass. Nature 423(6937):349CrossRef Harada SI, Rodan GA (2003) Control of osteoblast function and regulation of bone mass. Nature 423(6937):349CrossRef
4.
go back to reference Hernández-Cortés P, Monje A, Galindo-Moreno P, Catena A, Ortega-Oller I, Salas-Pérez J, Mesa F, Gómez-Sánchez R, Aguilar M, Aguilar D, O’Valle F (2014) An ex vivo model in human femoral heads for histopathological study and resonance frequency analysis of dental implant primary stability. BioMed Res Int 2014 Hernández-Cortés P, Monje A, Galindo-Moreno P, Catena A, Ortega-Oller I, Salas-Pérez J, Mesa F, Gómez-Sánchez R, Aguilar M, Aguilar D, O’Valle F (2014) An ex vivo model in human femoral heads for histopathological study and resonance frequency analysis of dental implant primary stability. BioMed Res Int 2014
5.
go back to reference Tarantino U, Cerocchi I, Celi M, Scialdoni A, Saturnino L, Gasbarra E (2009) Pharmacological agents and bone healing. Clin Cases Miner Bone Metab 6(2):144PubMedPubMedCentral Tarantino U, Cerocchi I, Celi M, Scialdoni A, Saturnino L, Gasbarra E (2009) Pharmacological agents and bone healing. Clin Cases Miner Bone Metab 6(2):144PubMedPubMedCentral
6.
go back to reference Bukata S (2011) Systemic administration of pharmacological agents and bone repair: what can we expect. Injury. 42(6):605–608CrossRef Bukata S (2011) Systemic administration of pharmacological agents and bone repair: what can we expect. Injury. 42(6):605–608CrossRef
7.
go back to reference Frishman WH, Saunders E (2011) β-Adrenergic blockers. J Clin Hypertens 13(9):649–653CrossRef Frishman WH, Saunders E (2011) β-Adrenergic blockers. J Clin Hypertens 13(9):649–653CrossRef
8.
go back to reference Bonnet N, Gadois C, McCloskey E, Lemineur G, Lespessailles E, Courteix D, et al. (2007). Gadois C, McCloskey E, Lemineur G, Lespessailles E, Courteix D, Benhamou CL. Protective effect of β blockers in post- menopausal women: influence on fractures, bone density, micro and macroarchitecture. p 1209–1216 Bonnet N, Gadois C, McCloskey E, Lemineur G, Lespessailles E, Courteix D, et al. (2007). Gadois C, McCloskey E, Lemineur G, Lespessailles E, Courteix D, Benhamou CL. Protective effect of β blockers in post- menopausal women: influence on fractures, bone density, micro and macroarchitecture. p 1209–1216
9.
go back to reference Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker K et al (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell. 111(2):305–317CrossRef Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker K et al (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell. 111(2):305–317CrossRef
10.
go back to reference Bonnet N, Benhamou C, Malaval L, Goncalves C, Vico L, Eder V et al (2008) Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions. J Cell Physiol 217(3):819–827 cellular physiology. 2008 Dec;217(3):819–27CrossRef Bonnet N, Benhamou C, Malaval L, Goncalves C, Vico L, Eder V et al (2008) Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions. J Cell Physiol 217(3):819–827 cellular physiology. 2008 Dec;217(3):819–27CrossRef
11.
go back to reference Sadr K, Aghbali A, Sadr M, Abachizadeh H, Azizi M, Abbasi M (2017) Effect of Beta-blockers on number of osteoblasts and osteoclasts in alveolar socket following tooth extraction in Wistar rats. J Dent 18(1):37 Sadr K, Aghbali A, Sadr M, Abachizadeh H, Azizi M, Abbasi M (2017) Effect of Beta-blockers on number of osteoblasts and osteoclasts in alveolar socket following tooth extraction in Wistar rats. J Dent 18(1):37
12.
go back to reference Bologna-Molina R, Damián-Matsumura P (2011) An easy cell counting method for immunohistochemistry that does not use an image analysis program. Histopathology. 217(3):801–803CrossRef Bologna-Molina R, Damián-Matsumura P (2011) An easy cell counting method for immunohistochemistry that does not use an image analysis program. Histopathology. 217(3):801–803CrossRef
13.
go back to reference O’loughlin P, Morr S, Bogunovic L, Kim AD, Park B, Lane JM (2008) Selection and development of preclinical models in fracture-healing research. JBJS 90:79–84 JBJS. 2008 Feb 1;90:79–84CrossRef O’loughlin P, Morr S, Bogunovic L, Kim AD, Park B, Lane JM (2008) Selection and development of preclinical models in fracture-healing research. JBJS 90:79–84 JBJS. 2008 Feb 1;90:79–84CrossRef
14.
go back to reference Guehennec LL, Goyenvalle E, Aguado E, Houchmand-Cuny M, Enkel B, Pilet P et al (2005) Small-animal models for testing macroporous ceramic bone substitutes. J Biomed Mater Res B Appl Biomater Offi J Soc Biomater Jpn Soc Biomater Aust Soc Biomater Korean Soc Biomater 72(1):69–78 Guehennec LL, Goyenvalle E, Aguado E, Houchmand-Cuny M, Enkel B, Pilet P et al (2005) Small-animal models for testing macroporous ceramic bone substitutes. J Biomed Mater Res B Appl Biomater Offi J Soc Biomater Jpn Soc Biomater Aust Soc Biomater Korean Soc Biomater 72(1):69–78
15.
go back to reference Schmitz J, Hollinger J (1986) The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res 205:205–299 Schmitz J, Hollinger J (1986) The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res 205:205–299
16.
go back to reference Rodrigues W, Madeira M, Silva TD, Clemente-Napimoga J, Miguel CB, da Silva VJD et al (2012) Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation. Br J Pharmacol 165(7):165–167CrossRef Rodrigues W, Madeira M, Silva TD, Clemente-Napimoga J, Miguel CB, da Silva VJD et al (2012) Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation. Br J Pharmacol 165(7):165–167CrossRef
17.
go back to reference Group BDW, Jr AA, Colburn WA, DeGruttola VG, DeMets DL, Downing G et al (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95CrossRef Group BDW, Jr AA, Colburn WA, DeGruttola VG, DeMets DL, Downing G et al (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95CrossRef
18.
go back to reference Han D, Han N, Xue F, Zhang P (2015) A novel specialized staging system for cancellous fracture healing, distinct from traditional healing pattern of diaphysis cortical fracture. Int J Clin Exp Med 8(1):1301PubMedPubMedCentral Han D, Han N, Xue F, Zhang P (2015) A novel specialized staging system for cancellous fracture healing, distinct from traditional healing pattern of diaphysis cortical fracture. Int J Clin Exp Med 8(1):1301PubMedPubMedCentral
19.
go back to reference Inoue S, Otsuka H, Takito J, Nakamura M (2018) Decisive differences in the bone repair processes of the metaphysis and diaphysis in young mice. Bone Reports 8:1–8CrossRef Inoue S, Otsuka H, Takito J, Nakamura M (2018) Decisive differences in the bone repair processes of the metaphysis and diaphysis in young mice. Bone Reports 8:1–8CrossRef
20.
go back to reference Iizuka T, Miller SC, Jr SM (1992) Alveolar bone remodeling after tooth extraction in normal and osteopetrotic (ia) rats. J Oral Pathol Med 21(4):150–155CrossRef Iizuka T, Miller SC, Jr SM (1992) Alveolar bone remodeling after tooth extraction in normal and osteopetrotic (ia) rats. J Oral Pathol Med 21(4):150–155CrossRef
21.
go back to reference Devlin H, Hoyland J, Newall JF, Ayad S (1997) Trabecular bone forma- tion in the healing of the rodent molar tooth extraction socket. J Bone Miner Res 12(12):2061–2067 12(12):2061–7CrossRef Devlin H, Hoyland J, Newall JF, Ayad S (1997) Trabecular bone forma- tion in the healing of the rodent molar tooth extraction socket. J Bone Miner Res 12(12):2061–2067 12(12):2061–7CrossRef
22.
go back to reference Vieira A, Repeke CE, Junior SD, Colavite PM, Biguestti CC, Oliveria R et al (2015) Intramembranous bone healing process subsequent to tooth extraction in mice: micro-computed tomography, histomorphometric and molecular characterization. PLoS One 10(5):e0128021CrossRef Vieira A, Repeke CE, Junior SD, Colavite PM, Biguestti CC, Oliveria R et al (2015) Intramembranous bone healing process subsequent to tooth extraction in mice: micro-computed tomography, histomorphometric and molecular characterization. PLoS One 10(5):e0128021CrossRef
23.
go back to reference Sabatini M, Aufdemorte T, Bonewald L, Mundy G (1988) Infusions of recombinant human interleukins 1 alpha and 1 beta cause hypercalcemia in normal mice. Proc Natl Acad Sci 85(14):5235–5239CrossRef Sabatini M, Aufdemorte T, Bonewald L, Mundy G (1988) Infusions of recombinant human interleukins 1 alpha and 1 beta cause hypercalcemia in normal mice. Proc Natl Acad Sci 85(14):5235–5239CrossRef
24.
go back to reference Roodman G (1992) Perspectives: interleukin-6: an osteotropic factor? J Bone Miner Res 7(5):475–478CrossRef Roodman G (1992) Perspectives: interleukin-6: an osteotropic factor? J Bone Miner Res 7(5):475–478CrossRef
25.
go back to reference Konda A, Mogi M, Koshihara Y, Togari A (2001) Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. Biochemical pharmacology. Biochem Pharmacol 61(3):319–326CrossRef Konda A, Mogi M, Koshihara Y, Togari A (2001) Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. Biochemical pharmacology. Biochem Pharmacol 61(3):319–326CrossRef
26.
go back to reference Tera T, Prado RF, de Marco A, Santamaria MP, Jardini MA (2014) The RANK/RANKL/OPG interaction in the repair of autogenous bone grafts in female rats with estrogen deficiency. Braz Oral Res 28(1):1–9CrossRef Tera T, Prado RF, de Marco A, Santamaria MP, Jardini MA (2014) The RANK/RANKL/OPG interaction in the repair of autogenous bone grafts in female rats with estrogen deficiency. Braz Oral Res 28(1):1–9CrossRef
27.
go back to reference Levasseur R, Dargent-Molina P, Sabatier JP, Marcelli C, Bréart G (2005) Beta-blocker use, bone mineral density, and fracture risk in older women: results from the Epidemiologie de l’Osteoporose prospective study. J Am Geriatr Soc 53(3):550–552CrossRef Levasseur R, Dargent-Molina P, Sabatier JP, Marcelli C, Bréart G (2005) Beta-blocker use, bone mineral density, and fracture risk in older women: results from the Epidemiologie de l’Osteoporose prospective study. J Am Geriatr Soc 53(3):550–552CrossRef
28.
go back to reference Reid IR, Gamble GD, Grey AB, Black DM, Ensrud KE, Browner WS, Bauer DC (2005) β-Blocker use, BMD, and fractures in the study of osteoporotic fractures. J Bone Miner Res 20(4):613–618CrossRef Reid IR, Gamble GD, Grey AB, Black DM, Ensrud KE, Browner WS, Bauer DC (2005) β-Blocker use, BMD, and fractures in the study of osteoporotic fractures. J Bone Miner Res 20(4):613–618CrossRef
29.
go back to reference Khosla S, Volkman TL, Thicke BS, Achenbach SJ, Atkinson EJ, Joyner MJ, et al. (2018). Sympathetic β 1-adrenergic signaling contributes to regulation of human bone metabolism. J Clin 128(11) Khosla S, Volkman TL, Thicke BS, Achenbach SJ, Atkinson EJ, Joyner MJ, et al. (2018). Sympathetic β 1-adrenergic signaling contributes to regulation of human bone metabolism. J Clin 128(11)
30.
go back to reference Zang Y, Tan Q, Ma X, Zhao X, Lei W (2016) Osteogenic actions of metoprolol in an ovariectomized rat model of menopause. Menopause. 23(9):1019–1025CrossRef Zang Y, Tan Q, Ma X, Zhao X, Lei W (2016) Osteogenic actions of metoprolol in an ovariectomized rat model of menopause. Menopause. 23(9):1019–1025CrossRef
Metadata
Title
The effects of intraperitoneal metoprolol administration on healing of bone defects in rat tibia: a pilot study
Authors
R. Al Alawy
H. Hammad
R. AlHabashneh
Publication date
01-03-2020
Publisher
Springer Berlin Heidelberg
Published in
Clinical Oral Investigations / Issue 3/2020
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI
https://doi.org/10.1007/s00784-019-02987-w

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