Ramelteon used to treat insomnia can reduce the occurrence of osteoporosis

Year 2021, , 164 - 170, 30.08.2021

Duygu Köse , Ahmet Köse , Zekai Halıcı , Muhammed Ali Gürbüz Adem Maman , Muhammed Yayla

https://doi.org/10.30565/medalanya.939161

Cited By: 1

Abstract

Aim: Melatonin promoted osteoblast differentiation and causes an increase in levels of markers of bone differentiation and proliferation. Ramelteon (RAMEL) activates melatonin receptors and binds to these receptors as non-selective. In this study, we investigated the preventive effects of the melatonin agonist RAMEL on osteoporosis by radiological, histological, and molecularly.

Methods: Groups 1: Control, Group 2: Osteoporosis: Overectomized group (OP), Group 3: OP + ramelteon 2 mg/kg, Group 4: OP + ramelteon 4 mg/kg. 24 animals underwent bilateral ovariectomy. RAMEL was administered orally once a day in the prophylactic treatment mode for 8 weeks, 6 weeks after ovariectomy.

Results: Fourteen weeks after ovariectomy, there was a significant reduction in femoral bone mineral density (BMD) (g/cm2) in the OP group compared to the control group. Compared to the OP group, RAMEL treatment significantly increased the BMD level (p<0.05). Bone matrix protein 2 (BMP2) and runt-related transcription factor 2 (RUNX2) mRNA levels were significantly lower in the OP group than in the control group (p<0.05). RUNX2 and BMP2 mRNA levels were significantly higher in the RAMEL treatment groups than in the OP group (p<0.05).

Conclusion: To take advantage of the peripheral effects of melatonin, RAMEL, a peripheral melatonin agonist, can be used to prevent osteoporosis. 

Keywords

melatonin;, bone;, rameltone;, osteoporosis;

Uykusuzluğu tedavi etmek için kullanılan Ramelteon, osteoporoz oluşumunu azaltabilir

Abstract

Amaç: Melatonin osteoblast farklılaşmasını teşvik eder ve kemik farklılaşması ve proliferasyon belirteçlerinin düzeylerinde artışa neden olur. Ramelteon (RAMEL) melatonin reseptörlerini aktive eder ve bu reseptörlere seçici olmayan şekilde bağlanır. Bu çalışmada melatonin agonisti RAMEL' in osteoporoz üzerindeki önleyici etkileri radyolojik, histolojik ve moleküler olarak araştırıldı.

Yöntem: Grup 1: Kontrol, Grup 2: Osteoporoz: Over eksizyonu yapılan grup (OP), Grup 3: OP + ramelteon 2 mg/kg, Grup 4: OP + ramelteon 4 mg/kg. 24 hayvana, bilateral ovariektomi uygulandı. RAMEL, ovariektomiden 6 hafta sonra, 8 hafta boyunca profilaktik tedavi modunda günde bir kez oral yoldan uygulandı.

Bulgular: Ovariektomiden on dört hafta sonra, kontrol grubuna kıyasla OP grubunda femoral kemik mineral yoğunluğunda (KMY) (g/cm2) anlamlı bir azalma oldu. OP grubu ile karşılaştırıldığında, RAMEL tedavisi BMD seviyesini önemli ölçüde artırdı (p<0.05). Bone matrix protein 2 (BMP2) and runt-related transcription factor 2 (RUNX2) mRNA seviyeleri OP grubunda kontrol grubuna göre anlamlı derecede düşüktü (p<0.05). RUNX2 ve BMP2 mRNA seviyeleri, RAMEL tedavi gruplarında OP grubuna göre anlamlı olarak daha yüksekti (p<0.05).

Sonuç: Melatoninin periferik etkilerinden yararlanmak için, bir periferik melatonin agonisti olan RAMEL, osteoporozu önlemek için kullanılabilir.

Keywords

Ramelteon, melatonin, osteoporoz;, kemik;

References

• 1. Yildirimturk S, Batu S, Alatli C, Olgac V, Firat D, Sirin Y. The effects of supplemental melatonin administration on the healing of bone defects in streptozotocin-induced diabetic rats. J Appl Oral Sci. 2016; 24:239-49. DOI: 10.1590/1678-775720150570
• 2. 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. DOI: 10.1111/jpi.12465
• 3. Park KH, Kang JW, Lee EM, Kim JS, Rhee YH, Kim M, Jeong SJ, Park YG, Kim SH. Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways. J Pineal Res. 2011; 51:187-94. DOI: 10.1111/j.1600-079X.2011.00875.x
• 4. Hakanson DO, Bergstrom WH. Pineal and adrenal effects on calcium homeostasis in the rat. Pediatr Res. 1990; 27:571-3. DOI: 10.1203/00006450-199006000-00006
• 5. Li T, Jiang S, Lu C, Yang W, Yang Z, Hu W, Xin Z, Yang Y. Melatonin: Another avenue for treating osteoporosis? J Pineal Res. 2019; 66:e12548. DOI: 10.1111/jpi.12548
• 6. Uslu S, Uysal A, Oktem G, Yurtseven M, Tanyalcin T, Basdemir G. Constructive effect of exogenous melatonin against osteoporosis after ovariectomy in rats. Anal Quant Cytol Histol. 2007; 29:317-25. PMID: 17987812
• 7. Halici M, Oner M, Guney A, Canoz O, Narin F, Halici C. Melatonin promotes fracture healing in the rat model. Eklem Hastalik Cerrahisi. 2010; 21:172-7. DOI: 10.1159/000492576
• 8. Conway S, Canning SJ, Howell HE, Mowat ES, Barrett P, Drew JE, Delagrange P, Lesieur D, Morgan PJ. Characterization of human melatonin mt(1) and MT(2) receptors by CRE-luciferase reporter assay. Eur J Pharmacol. 2000; 390:15-24. DOI: 10.1016/s0014-2999(99)00914-0
• 9. Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994; 13:1177-85. DOI: 10.1016/0896-6273(94)90055-8
• 10. Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI. Molecular pharmacology, regulation, and function of mammalian melatonin receptors. Front Biosci. 2003; 8:d1093-108. DOI: 10.2741/1089
• 11. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005; 27:101-10. DOI: 10.1385/ENDO:27:2:101
• 12. Sharan K, Lewis K, Furukawa T, Yadav VK. Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway. J Pineal Res. 2017; 63. DOI: 10.1111/jpi.12423
• 13. McGechan A, Wellington K. Ramelteon. CNS Drugs. 2005; 19:1057-65; discussion 66-7. DOI: 10.2165/00023210-200519120-00007
• 14. Hardeland R. Melatonin in aging and disease -multiple consequences of reduced secretion, options, and limits of treatment. Aging Dis. 2012; 3:194-225. PMID: 22724080
• 15. Chen W, Chen X, Chen AC, Shi Q, Pan G, Pei M, Yang H, Liu T, He F. Melatonin restores the osteoporosis-impaired osteogenic potential of bone marrow mesenchymal stem cells by preserving SIRT1-mediated intracellular antioxidant properties. Free Radic Biol Med. 2019. DOI: 10.1016/j.freeradbiomed.2019.10.412
• 16. 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; 59:221-9. DOI: 10.1111/jpi.12252
• 17. Kotlarczyk MP, Lassila HC, O'Neil CK, D'Amico F, Enderby LT, Witt-Enderby PA, Balk JL. 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; 52:414-26. DOI: 10.1111/j.1600-079X.2011.00956.x
• 18. Aydin A, Halici Z, Albayrak A, Polat B, Karakus E, Yildirim OS et al. Treatment with Carnitine Enhances Bone Fracture Healing under Osteoporotic and/or Inflammatory Conditions. Basic Clin Pharmacol Toxicol. 2015; 117:173-9. DOI: 10.1111/bcpt.12384
• 19. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T) Method. Methods. 2001; 25:402-8. DOI: 10.1006/meth.2001.1262
• 20. Nian H, Ma MH, Nian SS, Xu LL. Antiosteoporotic activity of icariin in ovariectomized rats. Phytomedicine. 2009; 16:320-6. DOI: 10.1016/j.phymed.2008.12.006
• 21. Oliver RA, Yu Y, Yee G, Low AK, Diwan AD, Walsh WR. Poor histological healing of a femoral fracture following 12 months of estrogen deficiency in rats. Osteoporos Int. 2013; 24:2581-9. DOI: 10.1590/1678-775720150570