Clinical Research Papers:

Role of melatonin combined with exercise as a switch-like regulator for circadian behavior in advanced osteoarthritic knee

Yunkyung Hong, Hyunsoo Kim, Seunghoon Lee, Yunho Jin, Jeonghyun Choi, Sang-Rae Lee, Kyu-Tae Chang and Yonggeun Hong _

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Oncotarget. 2017; 8:97633-97647. https://doi.org/10.18632/oncotarget.19276

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Yunkyung Hong1,2,3,4, Hyunsoo Kim2, Seunghoon Lee1,2,3,4, Yunho Jin2,3,4, Jeonghyun Choi2,3,4, Sang-Rae Lee5, Kyu-Tae Chang5 and Yonggeun Hong1,2,3,4

1 Department of Physical Therapy, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea

2 Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea

3 Biohealth Products Research Center (BPRC), Inje University, Gimhae, Korea

4 Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, Korea

5 National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea

Correspondence to:

Yonggeun Hong, email:

Kyu-Tae Chang, email:

Keywords: osteoarthritis, metabolic homeostasis, melatonin, exercise, circadian clock

Received: November 01, 2016 Accepted: May 12, 2017 Published: July 16, 2017


Here, we show the role of melatonin combined with or without exercise as a determinant of multicellular behavior in osteoarthritis. We address the relationship between the molecular components governing local circadian clock and changes in the osteoarthritic musculoskeletal axis. Melatonin was injected subcutaneously in animals with advanced knee osteoarthritis (OA) for 4 weeks. Concurrently, moderate treadmill exercise was applied for 30 min/day. Morphometric, histological, and gene/protein-level analyses were performed in the cartilage, synovium, bone, and gastrocnemius muscle. Primary cultured chondrocytes repeatedly exposed to TNF-α were used in an in vitro study. The symptoms of OA include gait disturbance, osteophyte formation, and abnormal metabolism of the extracellular matrix (ECM) of the cartilage. Low-level expression of clock genes was accompanied by aberrant changes in cartilage specimens.Nanomolar doses of melatonin restored the expression of clock-controlled genes and corrected the abnormal chondrocyte phenotype. Melatonin combined with or without exercise prevented periarticular muscle damage as well as cartilage degeneration. But prolonged melatonin administration promoted the proteolytic cleavage of RANKL protein in the synovium, leading to severe subchondral bone erosion. These musculoskeletal changes apparently occurred via the regulation of molecular clock components, suggesting a role of melatonin as a switch-like regulator for the OA phenotype.

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