Melatonin is a potential drug for the prevention of bone loss during space flight

September 03, 2019

[Background]

For proper and healthy metabolism of bone, appropriate stimuli are necessary. In outer space with microgravity, calcium is lost from bone and bone mass is reduced. Measurement of the bone density of astronauts before and after a long stay in outer space indicates bone mass loss. At the dawn of an era where astronauts are to stay for a long period of time in an international space station, it is an urgent task to elucidate changes of osteoblasts and osteoclasts under microgravity conditions and to perform research on potential drugs as remedies. Since it is difficult in outer space to use a cell culture system that meets in vivo conditions, other experimental models are necessary.

The present research group, consisting of 53 scientists from 33 institutions, led by scientists of Kanazawa University, Tokyo Medical and Dental University, Okayama University and University of Toyama, used cultured goldfish scales to investigate the mechanism of bone loss in space. A scale contains hydroxyapatite, a fundamental element of bone, and its bone matrix of two layers (osseous layer: a thin, well-calcified external layer; a fibrillary layer: a thick, partially calcified layer). A scale also has cells corresponding to osteoblasts and osteoclasts (Figure 1). Scales protect the surface of the fish body and play a role as a reservoir of calcium. With freshwater fish, the latter function is noteworthy; when salmon swim upstream to lay eggs, it is known that their scales get smaller in order to supply calcium to the eggs. To achieve this, osteoclasts release calcium from the scales. In addition, ground-basis experiments reveal that the responses of scales to hormones and extra-gravity due to centrifugation are very similar to those of mammalian bones. Furthermore, cultured scales may be considered to be an excellent experimental model for research of bone metabolism in outer space since scales are readily available and they can be used for experiments for about 10 days at a low temperature (4ºC) without exchanging culture media.

[Results]

Upon removal of a scale from fish skin, a new scale is regenerated. In this study, regenerated scales were used since their osteoblast and osteoclast activities are high. First it was shown that melatonin*1) was produced in scale osteoblasts and that melatonin synthesis decreased in space due to reduced expression of acetylserotonin O-methyltransferase, an enzyme important in melatonin synthesis (Figure 2a).

Further, melatonin functions in outer space were investigated by comparing scales cultured in a media supplemented with melatonin and those without. This experiment revealed that after a three-day culture in melatonin-free media, a number of osteoclasts fused together to form multinucleated, active osteoclasts. These active osteoclasts widened the grooves of a scale's osseous layer and enhanced bone resorption of scales. Moreover, the expression level of the Rankl*2) gene, a factor enhancing bone resorption, was elevated while the expression level of the Calcitonin*3) gene, a hormone suppressing bone resorption, was repressed. In contrast, in scales cultured in a media supplemented with melatonin, the expression level of Rankl was found to be repressed while Calcitonin expression was at a normal level, which coincided with suppressed gene expression levels for osteoclast functions (Figures 2b-e).

To our knowledge, no investigations have so far been performed on melatonin levels in outer space. We believe that one of the mechanisms of bone resorption under microgravity conditions could be a decrease of melatonin level to suppress CALCITONIN secretion (Figure 3). In fact, other research groups reported that the blood CALCITONIN level of a monkey decreased in outer space and that the CALCITONIN level in the blood of human subjects decreased after 120 days on a head-down tilt bed rest, a pseudo-microgravity experimental model.

The present research group confirmed in ground-basis experiments that scale osteoblasts produced CALCITONIN and that melatonin enhanced CALCITONIN secretion. Due to the limitation of rocket load, experiments on morphological changes of osteoclasts due to melatonin were not possible in outer space at this time; however, ground-basis experiments indicated suppression of morphological changes of activated osteoclasts by melatonin by using a three-dimensional clinostat, which produces pseudo-microgravity conditions. A research paper with these results was published in a high impact factor journal based on life science experiments performed in the Japanese Experiment Module for the first time.

As above, investigation of melatonin action on bones in outer space, which had been neglected so far, revealed that melatonin suppresses bone resorption by stimulating osteoblasts to secret CALCITONIN (Figure 3).

[Future prospects]

The present study indicates the possibility that melatonin could serve as a prophylactic drug to prevent bone loss of astronauts during their missions. Melatonin is expected to be used as a preventive and curative drug for loss of bones of astronauts in the future. The present research group performs in-space experiments on the functions of new melatonin derivatives on scales, which may lead to drug discovery of bone diseases.
-end-
[Glossary]

*1) Melatonin

Melatonin, N-acetyl-5-methoxytryptamine, is a hormone, an amine compound, secreted during the night. In vivo, it is synthesized from tryptophan via serotonin. Essential enzymes of melatonin synthesis include arylalkylamine N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT). Melatonin is primarily synthesized in and secreted from the pineal gland but it is known that other organs also produce melatonin. Melatonin is produced in vertebrates, invertebrates, plants and cyanobacteria; it is a hormone existing in a wide range of organisms.

*2) Rankl

Abbreviation of Receptor activator of nuclear factor kappa-B ligand. It is produced in osteoblasts and its binding to RANK (receptor activation of nuclear factor kappa-B) expressed in osteoclasts activates osteoclasts, enhancing bone resorption.

*3) CALCITONIN

CALCITONIN is a peptide hormone consisting of 32 amino acid residues, secreted from parafollicular cells of the thyroid gland of mammals and from the ultimobranchial gland of non-mammalian animals. Its primary action is to suppress osteoclast activities, inhibiting bone resorption. As a result, plasma calcium level is lowered. In the present study, we determined that CALCITONIN is secreted from osteoblasts in the goldfish scales.

Kanazawa University

Related Melatonin Articles from Brightsurf:

Worms reveal why melatonin promotes sleep
Melatonin is used as a dietary supplement to promote sleep and get over jet lag, but nobody really understands how it works in the brain.

Cleveland Clinic researchers identify melatonin as possible COVID-19 treatment
CLEVELAND - Results from a new Cleveland Clinic-led study suggest that melatonin, a hormone that regulates the sleep-wake cycle and is commonly used as an over-the-counter sleep aid, may be a viable treatment option for COVID-19.

Do urban fish exhibit impaired sleep?
Melatonin controls the body clock -- high melatonin levels make us feel tired in the evening.

Did cataract surgery change melatonin secretion in older patients?
The secretion of melatonin is an important indicator of the body's circadian rhythm.

Novel melatonin receptor molecules make possible therapies to adjust biological clock
Researchers have discovered through a vast and novel computational library the first molecules that can modulate circadian rhythms by binding with high selectivity to the MT1 melatonin receptor in the brain.

Light pollution can suppress melatonin production in humans and animals
Melatonin sets the internal clock. Researchers from Leibniz-Institute of Freshwater Ecology and Inland Fisheries (IGB) in an international team have analyzed data on the impact of light pollution on melatonin formation in humans and vertebrates.

Melatonin may not help prevent delirium after heart surgery
Delirium is observed in approximately 15% of hospitalised older adults, and it is more common in the critically ill and in those undergoing major surgery, such as heart surgery.

Melatonin is a potential drug for the prevention of bone loss during space flight
Melatonin could be a novel drug for preventing bone loss of astronauts during space flight.

Study looks at melatonin use, sleep patterns in school-age kids
This observational study used a study group of children from the Netherlands to examine how common was the use of melatonin and its association with sleep patterns in school-age children.

Researchers create the first maps of two melatonin receptors essential for sleep
An international team of researchers used an X-ray laser at the Department of Energy's SLAC National Accelerator Laboratory to create the first detailed maps of two melatonin receptors that tell our bodies when to go to sleep or wake up and guide other biological processes.

Read More: Melatonin News and Melatonin Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.