sdü tıp fak derg

Medical Journal of Süleyman Demirel University

2602-2109

Süleyman Demirel Üniversitesi

10.17343/sdutfd.979473

Clinical Sciences

Klinik Tıp Bilimleri

MELATONİN AGONİSTİ OLAN RAMELTEONUN METOTREKSAT KAYNAKLI KEMİK TOKSİSİTESİNE KARŞI KORUYUCU ETKİSİ

PROTECTIVE EFFECT OF THE RAMELTEON, A MELATONIN AGONIST, AGAINST METHOTREXATE-INDUCED BONE-TOXICITY

https://orcid.org/0000-0001-9088-3940

Dinçer

Recep

Süleyman Demirel Üniversitesi Tıp Fakültesi, Ortopedi ve Travmatoloji Anabilim Dalı

https://orcid.org/0000-0003-4600-2207

Baykal

Tuba

SULEYMAN DEMIREL UNIVERSITY

https://orcid.org/0000-0002-3879-9917

Kumbul Doğuç

Duygu

SULEYMAN DEMIREL UNIVERSITY

https://orcid.org/0000-0002-4671-9315

Sarman

Emine

SULEYMAN DEMIREL UNIVERSITY

https://orcid.org/0000-0002-7437-4465

Ceylan

Devran

SULEYMAN DEMIREL UNIVERSITY

03 01 2022

29 1 53 58 08 06 2021 09 06 2021

1994

Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi

AmaçMetotreksat (MTX) büyüme durması ve kemik mineralyoğunluğunun azalması dahil olmak üzere kemikmorbiditesine neden olan anti-metabolittir. Epifiz bezitarafından üretilen melatonin, insan kemik hücrelerindede birçok olumlu etkiye ve kemik üzerinde olumluetkilere sahiptir. Ramelteon (RMT), seçici olmayanbir melatonin reseptör agonistidir. Bu çalışmada, birmelatonin agonisti olan ramelteonun MTX kaynaklıkemik toksisitesi üzerinde koruyucu bir etkisinin olupolmadığını araştırdık.Gereç ve YöntemSıçanlar Grup 1 kontrol grubu olmak üzere 4 gruba ayrıldı;Grup 2 MTX grubu (20 mg/kg); Grup 3 MTX+RMT(20 mg/kg + 10 mg/kg); Grup 4 RMT (10 mg/kg).Ratlara gruplara göre ikinci gün oral ramelteon veintraperitoneal mtx uygulandı. 7 gün sonra uzun kemiklerhematoksilen-eozin (HE) boyama ile histolojikolarak ve Catepsin K ve RUN X2 boyama ile immünohistokimyasalolarak değerlendirildi. İstatistiksel analiziçin grupların immünhistokimyasal skorları gruplararasında karşılaştırıldı, bu amaçla SPSS-22.00 paketprogramı ile Oneway ANOVA Duncan testi kullanıldı.BulgularKemik doku kesitlerinin H&E boyamasında kontrolgrubu (grup I) ile deney grupları (grup II-grup III-grupIV) arasında anlamlı bir fark yoktu (p>0.05). CAT-Kve RUN-X immün boyamasında grupların hiçbirindepozitif boyanma gözlenmedi (p>0.05).SonuçRamelteonun, sağlam kemik dokusu üzerinde yüksekdoz metotreksatın neden olduğu kemik toksisitesinde,kemik döngüsünde, histopatolojik ve immünohistokimyasalolarak anabolik bir işlevi olmadığı gösterilmiştir.

ObjectiveMethotrexate (MTX) used anti-metabolite, causesbone morbidity, including growth arrest and reducedbone mineral density. Melatonin, produced by thepineal gland, has also multiple positive effects in humanbone cells, and positive effects on bone. Ramelteon(RMT) is a non-selective melatonin receptor agonist.In this study, we investigated whether ramelteon, amelatonin agonist, has a protective effect on MTXinducedbone toxicity.Material and MethodsThe rats divided into 4 groups, including Group 1control group; Group 2 MTX group (20 mg/kg); Group3 MTX+RMT (20 mg/kg + 10 mg/kg); Group 4 RMT (10mg/kg). Oral ramelteon and intraperitoneal mtx wereapplied to the rats on the second day according tothe groups. After 7 days, long bones were evaluatedhistologically with hematoxylin-eosin (HE) staining andimmunohistochemically with Catepsin K and RUN X2staining. For statistical analysis immunohistochemicalscores of the groups were compared between thegroups for this purpose, the Oneway ANOVA Duncantest was used by SPSS-22.00 package program.ResultsThere was no significant difference between thecontrol group (group I) and the experimental groups(group II-group III-group IV) in H&E staining of bonetissue sections (p>0.05). No positive staining wasobserved in any of the groups in CAT-K and RUN-Ximmunostaining (p>0.05).ConclusionIt was showed that ramelteon has no anabolicfunction in bone turnover, histopathological andimmunohistochemical, in bone toxicity induced byhigh-dose methotrexate on intact bone tissue.

METHOTREXATE RAMELTEON MELATONIN RUNX2 Catepsin K

Metotreksat Ramelteon Melatonin Katepsin-K RUNX2

SDU BAP

TSG-2020-8134

1. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-77.

2. Nilsson OS, Bauer FC, Brostrom LA, Nilsonne U. Effect of the antineoplastic agent methotrexate on experimental heterotopic new bone formation in rats. Cancer Res. 1984;44(4):1653-6.

3. Friedlaender GE, Tross RB, Doganis AC, Kirkwood JM, Baron R. Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg Am. 1984;66(4):602-7.

4. Demirel A, Kırnap M. Romatoid Artrit Tedavisinde Geleneksel Ve Güncel Yaklaşımlar. Sağlık Bilimleri Dergisi. 2010;19(1):74-84.

5. Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci. 2000;7(6):444-58.

6. Chen J, Zhang L, Li C, Chen R, Liu C, Chen M. Lipophilized Epigallocatechin Gallate Derivative Exerts Anti-Proliferation Efficacy through Induction of Cell Cycle Arrest and Apoptosis on DU145 Human Prostate Cancer Cells. Nutrients. 2019;12(1).

7. Maria S, Samsonraj RM, Munmun F, Glas J, Silvestros M, Kotlarczyk MP, et al. Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res. 2018;64(3).

8. Amstrup AK, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L. Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. J Pineal Res. 2015;59(2):221-9.

9. Kotlarczyk MP, Lassila HC, O'Neil CK, D'Amico F, Enderby LT, Witt-Enderby PA, et al. Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res. 2012;52(4):414-26.

10. McGechan A, Wellington K. Ramelteon. CNS Drugs. 2005;19(12):1057-65; discussion 66-7.

11. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021782s011lbl.pdf.

12. Komori T. Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res. 2010;339(1):189-95.

13. Komori T. Signaling networks in RUNX2-dependent bone development. J Cell Biochem. 2011;112(3):750-5.

14. Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem. 1996;271(21):12517-24.

15. Zaidi M, Troen B, Moonga BS, Abe E. Cathepsin K, osteoclastic resorption, and osteoporosis therapy. J Bone Miner Res. 2001;16(10):1747-9.

16. A. Refaiy EM, E. ElGanainy. Semiquantitative Smoothelin Expression in Detection of Muscle Invasion in Transurethral Resection and Cystectomy Specimens in Cases of Urinary Bladder Carcinoma. African Journal of Urology. 2011;17(1):6-10.

17. Singh JA, Saag KG, Bridges SL, Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25.

18. Romao VC, Lima A, Bernardes M, Canhao H, Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res. 2014;60(2-3):289-310.

19. Howard SC, McCormick, J., Pui, C. H., Buddington, R. K., & Harvey, R. D. . Preventing and Managing Toxicities of High-Dose Methotrexate. The oncologist. 2016;21(12):1471-82.

20. Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke MB, et al. Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab. 1998;83(9):3121-9.

21. Wheeler DL, Vander Griend RA, Wronski TJ, Miller GJ, Keith EE, Graves JE. The short- and long-term effects of methotrexate on the rat skeleton. Bone. 1995;16(2):215-21.

22. Roth JA, Kim BG, Lin WL, Cho MI. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem. 1999;274(31):22041-7.

23. Halici M, Oner M, Guney A, Canoz O, Narin F, Halici C. Melatonin promotes fracture healing in the rat model. Eklem Hastalik Cerrahisi. 2010;21(3):172-7.

24. Kose D, Kose A, Halici Z, Gurbuz MA, Aydin A, Ugan RA, et al. Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture. Eur J Pharmacol. 2020;887:173577.