The "internal clock" is becoming increasingly important in medical research. A disturbed day-night rhythm seems to be obviously bad for health. Researchers at the Julius Wolff Institute of the Charité now want to know whether this also applies to bone healing. In the long term, the project should lead to new therapies for bone fractures.
At night, when we sleep, it is particularly active: the bone metabolism, which permanently remodels our bones so that we have a high bone density, if possible, into old age. However, if we regularly turn night into day, these remodeling processes could be severely disrupted. This is indicated by large U.S. cohort studies, according to which shift workers have lower bone density than people with a normal day-night rhythm. This also increases their risk of osteoporosis and bone fractures.
"Want to close research gap"
But do bone fractures heal worse in shift workers? Although it has been known for years that the day-night rhythm, the so-called circadian rhythm, controls a number of metabolic processes in the body, including bone metabolism, there is still a large research gap. A research group from the Julius Wolff Institute at the Charité now wants to close this gap.
"We want to understand whether and how exactly fracture healing is influenced by the circadian rhythm," says Dr. Denise Jahn, a researcher at the Julius Wolff Institute "Only when we understand these processes in detail we can also develop new therapies for affected patients, and that is the overarching goal of our work."
Bones are a special organ system because they can heal almost without scarring. However, according to conservative estimates, delayed or no healing occurs in up to 15 percent of bone fractures; in many cases, the causes are unknown. Many of those affected remain impaired for years, and in older age a fracture can even be a cause of death due to the serious consequences of bed confinement. The need for research is therefore correspondingly great.
Preliminary data confirm assumption
Using mice in which a central gene of the circadian clock was switched off, the researchers were already able to show that bone healing was indeed impaired. Now they are trying to replicate this initial finding at the molecular level. For example, they are looking at which genes are expressed and regulated in the different stages of healing, staining cells and analyzing them with imaging techniques. Later, the researchers plan to compare the results with mice whose day-night rhythm is disturbed not by a gene knockout but by external influences such as light. From this, they can conclude what influence the rhythms in the brain and locally in the bone have on bone healing. Although mice, unlike humans, are nocturnal, the basic mechanisms of rhythmic metabolic activity are very similar. Therefore, disruption of the day-night rhythm in the central nervous system alters the same processes in the body.
Since the circadian clock is closely linked to stress signals in the body, it is even more important for the researchers to avoid unnecessary stress for the mice. For this reason, the mice are kept in groups and can occupy themselves with different materials, such as nail timbers, tubes and little houses in which they can build a nest with paper towels. With the help of so-called tunnel handling, in which the mice learn to run into a tube with which they can be placed in a new cage, negative experiences, such as being caught by the tail, are to be avoided.
"In order to understand the connections between bone healing and circadian rhythms, we need a living organism with blood flow, a natural diversity of cells, an immune system and, above all, a central nervous system, because the circadian clock is anchored in the brain," biologist Jahn emphasizes. In the future, modulators for circadian rhythms will be tested on the model, as well as healthy sleep hygiene, in order to find starting points for possible therapies.
And of course, a clinical study with shift workers is also being planned. The demands on this are high, however, as bone healing depends on many factors that need to be recorded and assessed for each individual. A small cohort of patients with well-described fracture healing will make a start.
Research results likely relevant to other injuries
"We are currently looking at all of this only for the bone fracture, but we believe that our results could also be relevant for other injuries," says Jahn. In that respect, she says, research into the role of the circadian clock in bone healing is part of a large, new branch of research that is becoming increasingly important.
The role of the circadian clock has already been recognized in cancer medicine. There, they are just beginning to incorporate sleep hygiene into therapy concepts. "It's quite possible that we, too, will soon be telling our patients after a bone fracture that they should please always go to sleep at the same time in the evening over the next few weeks in order to promote wound healing," says Denise Jahn. "But to get there, we need to do more research."
(Text: Beatrice Hamberger)
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Julius Wolff Institut (JWI) - Center for Musculoskeletal Biomechanics and Regeneration
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