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Review
. 2019 Sep 8;8(9):1415.
doi: 10.3390/jcm8091415.

Physiological and Pathological Role of Circadian Hormones in Osteoarthritis: Dose-Dependent or Time-Dependent?

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Free PMC article
Review

Physiological and Pathological Role of Circadian Hormones in Osteoarthritis: Dose-Dependent or Time-Dependent?

Farhad Md Hossain et al. J Clin Med. .
Free PMC article

Abstract

Osteoarthritis (OA), the most common form of arthritis, may be triggered by improper secretion of circadian clock-regulated hormones, such as melatonin, thyroid-stimulating hormone (TSH), or cortisol. The imbalance of these hormones alters the expression of pro-inflammatory cytokines and cartilage degenerative enzymes in articular cartilage, resulting in cartilage erosion, synovial inflammation, and osteophyte formation, the major hallmarks of OA. In this review, we summarize the effects of circadian melatonin, TSH, and cortisol on OA, focusing on how different levels of these hormones affect OA pathogenesis and recovery with respect to the circadian clock. We also highlight the effects of melatonin, TSH, and cortisol at different concentrations both in vivo and in vitro, which may help to elucidate the relationship between circadian hormones and OA.

Keywords: circadian clock; cortisol; melatonin; osteoarthritis; thyroid-stimulating hormone.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The synthesis of melatonin, thyroid-stimulating hormone (TSH), and cortisol, depending on circadian rhythm. The expression of cortisol, a steroid hormone produced in the adrenal gland, is tightly regulated by circadian rhythms in various mammals, including humans. The primary rhythm of this cycle is controlled by the suprachiasmatic nucleus (SCN), located in the hypothalamus. The secretion pattern of cortisol is coordinated by the hypothalamic–pituitary–adrenal (HPA) axis and the hippocampus. This HPA axis receives input from the SCN, from which it controls corticotrophin-releasing hormone (CRH) release in the paraventricular nucleus. From there, adrenocorticotrophic hormone (ACTH) is released from the corticotropes in the anterior pituitary by stimulating CRH. In normal individuals, cortisol levels fall to low or even undetectable levels around midnight, followed by peak expression around at 08:30.
Figure 2
Figure 2
In vitro studies show that high concentrations of melatonin lead to increases in reactive oxygen species (ROS) expression, oxidative stress, and inflammatory cytokines, with low concentrations of melatonin exhibiting the opposite effects, including enhanced antioxidant action and reduced ROS expression. Low concentrations may inhibit cartilage degradation by regulating pro-inflammatory cytokines and ROS.
Figure 3
Figure 3
Endogenous melatonin suppresses excessive reactive oxygen species (ROS) production and pro-inflammatory cytokines, and increases antioxidant action during osteoarthritis (OA). In addition, pharmacological treatment with melatonin also shows beneficial effects that protect extracellular matrix (ECM) molecules in articular cartilage.
Figure 4
Figure 4
TSH stimulates the thyroid gland to secrete T3 and T4. TSH decreases Col2a1 and SOX-9 expression through activation of ERK, MAPK, and P38, as well as enhancing the expression of matrix metalloproteinase (MMP)-13 and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-5, which are responsible for cartilage degradation. The circadian clock-controlled TSH hormone shows peak levels shortly after midnight (02:00–04:00), which may promote OA. In contrast, lower levels, typically seen between 14:00 and 17:00, may inhibit OA progression.

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