Skip to main content

Advertisement

SpringerLink
Log in

Melatonin ameliorates osteoarthritis rat cartilage injury by inhibiting matrix metalloproteinases and JAK2/STAT3 signaling pathway

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

A Correction to this article was published on 30 May 2023

This article has been updated

Abstract

Objective

To observe the effect of melatonin intervention on rat knee osteoarthritis (KOA) model and explore its mechanism.

Methods

A total of 81 Sprague–Dawley (SD) rats were employed. Haematoxylin and eosin (H&E) staining and safranin o-solid green staining were used to observe the changes of pathology in KOA, and inflammation factors in serum were detected by enzyme-linked immunosorbent assay (ELISA), type II collagen (Col-II) was detected by immunohistochemistry, chondrocyte apoptosis was detected by TdT-mediated dUTP nick-end labeling (TUNEL). The expression of matrix metalloproteinases (MMPs) and JAK2/STAT3 signaling were detected by western blot.

Results

Melatonin treatment ameliorated the histomorphology of knee joint in rats compared to the model group. The contents of TNF-α, IL-6, and IL-1β in serum were decreased after melatonin treatment. In addition, compared to the model group, the positive expression of Col-II increased, the chondrocyte apoptosis decreased after melatonin treatment. Interestingly, the expression levels of MMP3, MMP9, MMP13, p-JAK2 and p-STAT3 decreased (p < 0.05). Importantly, melatonin combined with AG490 is significantly ameliorates histomorphology of knee joint, reduced cartilage loss compared with melatonin treatment alone.

Conclusions

Melatonin treatment can effectively diminish the cartilage injury. Its mechanism may be related to protect the articular cartilage by reducing the release of inflammatory factors, inhibit the expression of MMPs and JAK2/STAT3 signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Change history

References

  • Abramoff B, Caldera FE (2020) Osteoarthritis: pathology, diagnosis, and treatment options. Med Clin N Am 104:293–311

    Article  PubMed  Google Scholar 

  • Burrage PS, Mix KS, Brinckerhoff CE (2006) Matrix metalloproteinases: role in arthritis. Front Biosci 11:529–543

    Article  CAS  PubMed  Google Scholar 

  • Cao C, Wu F, Niu X et al (2020) Cadherin-11 cooperates with inflammatory factors to promote the migration and invasion of fibroblast-like synoviocytes in pigmented villonodular synovitis. Theranostics 10:10573–10588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen F, Liu H, Wang X et al (2020) Melatonin activates autophagy via the NF-κB signaling pathway to prevent extracellular matrix degeneration in intervertebral disc. Osteoarthr Cartil 28:1121–1132

    Article  CAS  Google Scholar 

  • Cho JH, Bhutani S, Kim CH et al (2021) Anti-inflammatory effects of melatonin: a systematic review and meta-analysis of clinical trials. Brain Behav Immun 93:245–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fernihough J, Gentry C, Malcangio M et al (2004) Pain related behaviour in two models of osteoarthritis in the rat knee. Pain 112:83–93

    Article  PubMed  Google Scholar 

  • Gao B, Gao W, Wu Z et al (2018) Melatonin rescued interleukin 1β-impaired chondrogenesis of human mesenchymal stem cells. Stem Cell Res Ther 9:162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hardeland R (2018) Melatonin and inflammation—story of a double-edged blade. J Pineal Res 65(4):e12525

    Article  PubMed  Google Scholar 

  • Hosseinzadeh A, Kamrava SK, Joghataei MT et al (2016) Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin. J Pineal Res 61:411–425

    Article  CAS  PubMed  Google Scholar 

  • Hunter DJ, March L, Chew M (2020) Osteoarthritis in 2020 and beyond: a lancet commission. Lancet 396:1171–1172

    Article  Google Scholar 

  • Jahanban-Esfahlan R, Mehrzadi S, Reiter RJ et al (2018) Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes. Br J Pharmacol 175:3230–3238

    Article  CAS  PubMed  Google Scholar 

  • Jia X, Ma J, Chen X et al (2022) Immunoregulation and anti-metalloproteinase bioactive injectable polysalicylate matrix gel for efficiently treating osteoarthritis. Mater Today Bio 15:100277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jo S, Wang SE, Lee YL et al (2018) IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis. Arthritis Res Ther 20:115

    Article  PubMed  PubMed Central  Google Scholar 

  • Lai Z, Lee S, Chen Y et al (2021) Comparison of whole-body vibration training and quadriceps strength training on physical function and neuromuscular function of individuals with knee osteoarthritis: a randomised clinical trial. J Exerc Sci Fit 19:150–157

    Article  PubMed  PubMed Central  Google Scholar 

  • Lan H, Su Y, Liu Y, Deng C et al (2019) Melatonin protects circulatory death heart from ischemia/reperfusion injury via the JAK2/STAT3 signalling pathway. Life Sci 228:35–46

    Article  CAS  PubMed  Google Scholar 

  • Lim HD, Kim YS, Ko SH et al (2012) Cytoprotective and anti-inflammatory effects of melatonin in hydrogen peroxide-stimulated CHON-001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway. J Pineal Res 53(3):225–237

    Article  CAS  PubMed  Google Scholar 

  • Lyu S, Ji B, Gao W et al (2017) Effects of Angelicae pubescentis and Loranthi decotion on repairing knee joint cartilages in rats. J Orthop Surg Res 12:189

    Article  PubMed  PubMed Central  Google Scholar 

  • Namyen J, Permpoonputtana K, Nopparat C et al (2020) Protective effects of melatonin on methamphetamine-induced blood-brain barrier dysfunction in rat model. Neurotox Res 37(640–660):11

    Google Scholar 

  • Prasad AP, Nardo L, Schooler J et al (2013) T1ρ and T2 relaxation times predict progression of knee osteoarthritis. Osteoarthr Cartil 21(1):69–76

    Article  CAS  Google Scholar 

  • Pritzker KP, Gay S, Jimenez SA et al (2006) Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage 14(1):13–29

    Article  CAS  PubMed  Google Scholar 

  • Radogna F, Diederich M, Ghibelli L (2010) Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol 80(12):1844–1852

    Article  CAS  PubMed  Google Scholar 

  • Tarocco A, Caroccia N, Morciano G et al (2019) Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis 10(4):317

    Article  PubMed  PubMed Central  Google Scholar 

  • Vassão PG, Parisi J, Penha TFC et al (2021) Association of photobiomodulation therapy (PBMT) and exercises programs in pain and functional capacity of patients with knee osteoarthritis (KOA): a systematic review of randomized trials. Lasers Med Sci 36:1341–1353

    Article  PubMed  Google Scholar 

  • Wang T, He C (2018) Pro-inflammatory cytokines: the link between obesity and osteoarthritis. Cytokine Growth Factor Rev 44:38–50

    Article  PubMed  Google Scholar 

  • Wang L, Wang C, Choi WS (2022) Use of melatonin in cancer treatment: where are we? Int J Mol Sci 23(7):3779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing CH, Wang Y, Liu JC et al (2021) Melatonin reverses mitochondria dysfunction and oxidative stress-induced apoptosis of Sudan I-exposed mouse oocytes. Ecotoxicol Environ Saf 225:112783

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Lv H, Li X et al (2018) Danshen attenuates cartilage injuries in osteoarthritis in vivo and in vitro by activating JAK2/STAT3 and AKT pathways. Exp Anim 67:127–137

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Duan W, Jin Z et al (2013) JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury. J Pineal Res 55:275–286

    Article  CAS  PubMed  Google Scholar 

  • Yao ZZ, Hu AX, Liu XS (2017) DUSP19 regulates IL-1β-induced apoptosis and MMPs expression in rat chondrocytes through JAK2/STAT3 signaling pathway. Biomed Pharmacother 96:1209–1215

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Lin J, Zhou X et al (2019) Melatonin prevents osteoarthritis-induced cartilage degradation via targeting MicroRNA-140. Oxid Med Cell Longev 2019:9705929

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhen G, Liang W, Jia H et al (2020) Melatonin relieves sepsis-induced myocardial injury via regulating JAK2/STAT3 signaling pathway. Minerva Med. https://doi.org/10.23736/S0026-4806.20.06626-4

    Article  PubMed  Google Scholar 

  • Zhou X, Zhang Y, Hou M et al (2022) Melatonin prevents cartilage degradation in early-stage osteoarthritis through activation of miR-146a/NRF2/HO-1 axis. J Bone Miner Res 37(5):1056–1072

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the Project of Yantai Science and Technology Innovation and Development (2020MSGY083).

Author information

Author notes

  1. Zhongyuan Zhao and Benjun Bi contributed equally to this work.

Authors and Affiliations

  1. Department of Articulation Surgery, Yantaishan Hospital, Yantai, Shandong, China

    Zhongyuan Zhao & Yuchi Zhao

  2. Department of Hand and Foot Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China

    Benjun Bi

  3. Department of Sports Medicine, Yantaishan Hospital, Yantai, Shandong, China

    Gong Cheng, Hao Wu, Mingdi Zheng & Zhilin Cao

Authors
  1. Zhongyuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benjun Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuchi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingdi Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhilin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Zhongyuan Zhao, Benjun Bi, Gong Cheng, Yuchi Zhao, Hao Wu, Mingdi Zheng, Zhilin Cao. The first draft of the manuscript was written by Zhongyuan Zhao, Benjun Bi, Zhilin Cao and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhilin Cao.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Ethics approval

This study was approved by the animal ethics committee of Yantaishan Hospital, and all experimental procedures were conducted according to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, NIH).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Z., Bi, B., Cheng, G. et al. Melatonin ameliorates osteoarthritis rat cartilage injury by inhibiting matrix metalloproteinases and JAK2/STAT3 signaling pathway. Inflammopharmacol 31, 359–368 (2023). https://doi.org/10.1007/s10787-022-01102-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-022-01102-y

Keywords

Search

Navigation