J Pineal Res. 2014 Aug;57(1):53-66. doi: 10.1111/jpi.12143. Epub 2014 Jun 7.

Salutary effects of melatonin combined with treadmill exercise on cartilage damage.


Hong Y, Kim H, Lee Y, Lee S, Kim K, Jin Y, Lee SR, Chang KT, Hong Y.

Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea; Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea; Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea.



Osteoarthritis (OA) is a major cause of disability in the adult population. The purpose of this study was to evaluate the effects of melatonin with graded dosage on extracellular matrix synthesis and cellular death in response to cartilage damage in vitro and in vivo. TNF-α reduced the viability of primary cultured chondrocytes and extracellular matrix protein, but melatonin at concentrations of 1 μm and 1 nm restored them. Rats with knee instability induced by intra-articular collagenase were used for the in vivo study. Joint parameters were significantly augmented in the collagenase injection-only group but not in the melatonin-alone or melatonin+exercise groups, as cartilage degeneration progressed. Serum TNF-α and IL-6 were upregulated by collagenase injection, which was attenuated by melatonin with and without exercise in the early phase. TGF-β1 mRNA was either conserved or enhanced by melatonin with and without exercise at the early phase. In particular, melatonin combined with exercise dramatically decreased the expression of not only catabolic mediators but also cellular death markers with lower mineralization. At the advanced phase, prolonged melatonin treatment promoted mineralization through caspase-3-mediated chondrocyte apoptosis. However, co-intervention induced extracellular matrix remodeling through increases in IL-6, EPAS-1, and MMP-13. Reconstructed micro-CT images showed that collagenase injection induced subchondral bone erosion, formation of parameniscal osteophytes, and reduction of trabecular bone thickness regardless of the intervention, which was minimized by combined intervention. In conclusion, we suggest that melatonin with treadmill exercise may have both preventive and synergistic effects on rescue from cartilage degeneration and is more effective in the initial phase.

KEYWORDS: MMP-13; cartilage degeneration; exercise; melatonin; type II collagen

PMID: 24816289



Melatonin is a well-known hormone produced by pineal gland and famous for its various roles involved in oxidative stress, inflammation, and circadian rhythm. Because melatonin is also appeared to regulate chondrogenic differentiation of mesenchymal stem cells (MSCs) [1], it has been suggested as a putative candidate for cartilage repair in osteoarthritis (OA). OA, which is categorized as degenerative joint disorder, has pathological characteristics such as chondrocyte death, extracellular matrix (ECM) loss, and osteophyte formation. Articular cartilage consists of sparse cell population (chondrocytes) and surrounded ECM network. The latter primarily includes type II collagen (COL2A1) and glycosaminoglycan (GAG), which is important for cell to cell interaction [2]. Of numerous catabolic enzymes, matrix metalloproteinase-13 (MMP-13) is the best to degrade or remodel OA cartilage. But recent studies have suggested that melatonin might suppress MMP activity in various diseases [3]. Therefore, we hypothesized that melatonin plus exercise might suppress MMP-13 activity in ongoing cartilage damage. As it turns out, our hypotheses were only partially correct. Melatonin combined with exercise (MT+Ex), at low impact, inhibits TNF-α mediated MMP-13 transcription through TGF-β1 up-regulation at very early OA (Figure), but its application for long-term is inappropriate to block the intricate processes involved in chondrocyte hypertrophy during OA progression. Based on their preventive effects, we further examine the therapeutic efficacy of combined intervention in OA cartilage now.



Figure. Diagram showing how melatonin combined with exercise induces delayed cartilage damage through blockade of catabolic processes.



  1. Gao W, Lin M, Liang A, et al. Melatonin enhances chondrogenic differentiation of human mesenchymal stem cells. J Pineal Res. 56(1):62-70.
  2. Hashimoto M, Nakasa T, Hikata T, et al. Molecular network of cartilage homeostasis and osteoarthritis. Med Res Rev. 28(3):464-81.
  3. Swarnakar S, Paul S, Singh LP, et al. Matrix metalloproteinases in health and disease: regulation by melatonin. J Pineal Res. 50(1):8-20.






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