Tag: 21/6/24

Categories : Skeletal SystemTags :

New Study Reveals Promising Drug Target for Osteoporosis Treatment

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Photo by Mehmet Turgut Kirkgoz on Unsplash

In a recent study published in Journal of Cellular Physiology, researchers from Tokyo University of Science discovered a new target for the treatment of osteoporosis, which is responsible for 8.9 million fractures globally each year. They focused on improving a common bone-strengthening drug, teriparatide, which has a tendency to also increase bone resorption. By targeting a newly identified gene, they were able to suppress teriparatide’s bone resorption effect.

Induction of parathyroid hormone (PTH) signalling using the synthetic PTH-derived peptide – teriparatide, has demonstrated strong bone-promoting effects in patients with osteoporosis. These effects are mediated by osteogenesis, the process of bone formation involving the differentiation and maturation of bone-forming cells called osteoblasts. However, PTH induction is also associated with the differentiation of macrophages into osteoclasts, which resorb bone. Although, bone remodelling by osteoblasts and osteoclasts is crucial for maintaining skeletal health, PTH-induced osteoclast differentiation can decrease treatment efficacy in patients with osteoporosis. However, precise molecular mechanisms underlying the dual action of PTH signaling in bone remodelling are not well understood.

To bridge this gap, Professor Tadayoshi Hayata and Ms Chisato Sampei, from Tokyo University of Science, along with their colleagues, conducted a series of experiments to identify druggable target genes downstream of PTH signalling in osteoblasts. Explaining the rationale behind their study , corresponding author, Prof. Hayata says, “In Japan, it is estimated that 12.8 million people, or one in ten people, suffer from osteoporosis, which can significantly deteriorate their quality of life. Teriparatide is classified as a drug that promotes bone formation, but it also promotes bone resorption, which may limit bone formation. However, the full scope of its pharmacological action remains unknown.”

The researchers treated cultured mouse osteoblast cells and mice with teriparatide. They then assessed gene expression changes induced by PTH in both the cultured cells and bone cells isolated from the femurs of the treated animals, using advanced RNA-sequencing analysis. Among several upregulated genes, they identified a novel PTH-induced gene – ‘Gprc5a’, encoding an orphan G protein-coupled receptor, which has been previously explored as a therapeutic target. However, its precise role in osteoblast differentiation had not been fully understood.

PTH induction has been known to activate the cyclic adenosine monophosphate (cAMP) and protein kinase C (PKC) signaling pathways. Interestingly, the team found that in addition to PTH induction, activation of cAMP and PKC also resulted in overexpression of Gprc5a, albeit to a lesser extent, underscoring the potential involvement of other molecular pathways. Notably, upregulation of Gprc5a was suppressed upon inhibition of transcription, but, remained unaffected upon suppressing protein synthesis, suggesting that Gprc5a could be transcribed early on in response to PTH signaling and serves as a direct target gene.

Furthermore, the researchers examined the effect of Gprc5a downregulation on osteoblast proliferation and differentiation. Notably, while PTH induction alone did not affect cell proliferation, Gprc5a knockdown resulted in an increase in the expression of cell-cycle-related genes and osteoblast differentiation markers. These findings suggest that Gprc5a suppresses osteoblast proliferation and differentiation.

Diving deeper into the molecular mechanisms underlying the effects of Gprc5a, in PTH-induced osteogenesis, the researchers identified Activin receptor-like kinase 3 (ALK3) – a bone morphogenetic protein (BMP) signalling pathway receptor, as an interacting partner of Gprc5a. In line with their speculation, overexpression of Gprc5a indeed, led to suppression of BMP signalling via receptors including ALK3.

Overall, these findings reveal that Gprc5a – a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation, by partially suppressing BMP signaling. Gprc5a can thus, be pursued as a novel therapeutic target while devising treatments against osteoporosis. The study sheds light on the complex process of bone remodeling and explains the bone-promoting and bone-resorbing effects of PTH signaling.

“Our study shows Gprc5a may function as a negative feedback factor for the bone formation promoting effect of teriparatide. Suppressing Gprc5a function may, therefore, increase the effectiveness of teriparatide in non-responding patients. In the future, we hope that our research will lead to improved quality of life and healthy longevity for people suffering from osteoporosis,” concludes Prof Hayata.

Source: Tokyo University of Science

Categories : Mental HealthTags :

How Stress Saps Cognitive Reserves, Increasing Dementia Risk

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Photo by Alex Green on Pexels

While mentally stimulating activities and life experiences can improve cognition in memory clinic patients, stress undermines this beneficial relationship. This is according to a new study published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Researchers in the late 1980s found that some individuals who showed no apparent symptoms of dementia during their lifetime had brain changes consistent with an advanced stage of Alzheimer’s disease. 

It has since been postulated that so-called cognitive reserve might account for this differential protective effect in individuals. 

Cognitively stimulating and enriching life experiences and behaviours such as higher educational attainment, complex jobs, continued physical and leisure activities, and healthy social interactions help build cognitive reserve. 

Increased risk of dementia

However, high or persistent stress levels are associated with reduced social interactions, impaired ability to engage in leisure and physical activities, and an increased risk of dementia.  

Researchers from Karolinska Institutet have now examined the association between cognitive reserve, cognition, and biomarkers for Alzheimer’s disease in 113 participants from the memory clinic at the Karolinska University Hospital, Huddinge, Sweden. 

They also examined how this association is modified by physiological stress (cortisol levels in saliva) and psychological (perceived) stress. 

Greater cognitive reserve was found to improve cognition, but interestingly, physiological stress appeared to weaken the association.  

“These results might have clinical implications as an expanding body of research suggests that mindfulness exercises and meditation may reduce cortisol levels and improve cognition,” says the study’s lead author Manasa Shanta Yerramalla, researcher at the Department of Neurobiology, Care Sciences and Society. “Different stress management strategies could be a good complement to existing lifestyle interventions in Alzheimer’s prevention.” 

The relatively small sample of participants reduces the possibility of drawing robust conclusions, but the results are generalisable to similar patient groups.  

Link between sleep and cognition 

Moreover, since stress disrupts sleep, which in turn disrupts cognition, the researchers controlled for sleeping medications; they did not, however, consider other aspects of sleep that might impair cognition. 

“We will continue to study the association between stress and sleeping disorders and how it affects the cognitive reserve in memory clinic patients,” says Dr Yerramalla. 

Source: Karolinska Institutet

Categories : Obstetrics & GynaecologyTags :

First Menstrual Periods are Arriving Earlier for Younger Generations

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Photo by Marta Branco

The average age at menarche, the first menstrual period, has been decreasing among younger generations in the US, especially those belonging to racial minorities and lower socioeconomic statuses, according to a new study led by researchers at Harvard T.H. Chan School of Public Health. It also found that the average time it takes for the menstrual cycle to become regular is increasing.

The study, published in JAMA Network Open, is the latest publication from the Apple Women’s Health Study, a longitudinal study of menstrual cycles, gynaecological conditions, and overall women’s health conducted by Harvard Chan School, the National Institute of Environmental Health Sciences, and Apple.

“Our findings can lead to a better understanding of menstrual health across the lifespan and how our lived environment impacts this critical vital sign,” said co-principal investigator Shruthi Mahalingaiah, assistant professor of environmental, reproductive, and women’s health at Harvard Chan School.

While previous studies have shown trends towards earlier menarche over the past five decades, data has been limited on how these trends present within different racial groups and socioeconomic statuses. Additionally, few studies have had sufficient data to identify any trends regarding time to menstrual cycle regularity.

The researchers used the Apple Women’s Health Study’s large, diverse dataset to fill this research gap. The 71 341 participants who enrolled between November 2018 and March 2023 self-reported the age at which they first began menstruating and their race and socioeconomic status. The researchers divided the participants into five age brackets: born between 1950–1969, 1970–1979, 1980–1989, 1990–1999, and 2000-2005. Ages of menarche were defined as early (younger than 11 years old), very early (younger than 9), and late (ages 16 and above). A subset of participants (61 932) self-reported the time it took for their menstrual cycle to become regular and were divided into five categories: up to two years, between three and four years, longer than five years, hasn’t become regular, or became regular with use of hormones. Another subset (9865) provided their body mass index (BMI) at their age of menarche.

The study found that as birth year increased (meaning younger participants), average age at menarche decreased and time from menarche to menstrual cycle regularity increased. Among participants born from 1950–1969, the average age at menarche was 12.5 years, and the rates of early and very early menarche were 8.6% and 0.6%, respectively. Among participants born from 2000–2005, the average age of menarche was 11.9 years, and the rates of early and very early menarche were 15.5% and 1.4%, respectively. Across the two groups, the percentage of participants who reached menstrual cycle regularity within two years of menarche decreased from 76% to 56%. The researchers observed that these trends were present among all sociodemographic groups but were most pronounced among the participants who identified as Black, Hispanic, Asian, or mixed race, and who rated themselves as belonging to a low socioeconomic status.

The findings showed that BMI at age of menarche could explain part of the trend toward periods starting earlier. Other possible factors that might explain the trend include dietary patterns, psychological stress and adverse childhood experiences, and environmental factors such as endocrine-disrupting chemicals and air pollution.

“Continuing to investigate early menarche and its drivers is critical,” said corresponding author Zifan Wang, postdoctoral research fellow in Harvard Chan School’s Department of Environmental Health. “Early menarche is associated with higher risk of adverse health outcomes, such as cardiovascular disease and cancer. To address these health concerns – which our findings suggest may begin to impact more people, with disproportionate impact on already disadvantaged populations – we need much more investment in menstrual health research.”

The authors noted some limitations to the study, including that it relies heavily on retrospective self-reporting.

Source: Harvard T.H. Chan School of Public Health

Categories : GenderTags :

Women’s Mental Agility is Better During Their Periods

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Photo by Ashley Williams

New research involving female football players has shown that they react more quickly and accurately during their periods, despite them feeling that they perform worse. The study, published in Neuropsychologia, is the first to assess sport-related cognition during the menstrual cycle and is part of a larger research project supported by the FIFA Research Scholarship.

The findings, from University College London, act as a proof-of-principle that specific types of cognition fluctuate throughout the menstrual cycle, which could have implications for injury and other aspects of women’s health.

Previous sports medicine research has shown that women seem to be at greater risk of sport-related injury during the luteal phase, which is the time between ovulation and menstruation. This is possibly related to the significant hormonal changes that occur throughout the menstrual cycle. But precisely how these changes are linked to an increased likelihood of injury are unknown at present.

In this study, researchers at UCL and ISEH collected reaction time and error data from 241 participants who completed a battery of cognitive tests 14 days apart. Participants also completed a mood scale and a symptom questionnaire twice. Period-tracking apps were used to estimate which phase of their cycle the participants were in when they took the tests.

The tests were designed to mimic mental processes that are typical in team sports. In one test, participants were shown smiling or winking faces and asked to press the space bar only when they saw a smiley face, to test inhibition, attention, reaction time and accuracy. In another, they were asked to identify mirror images in a 3D rotation task, which assesses spatial cognition. A task that asked them to click when two moving balls collide on screen measured spatial timing.

Though participants reported feeling worse during menstruation and perceived that this negatively impacted their performance, their reaction times were faster and they made fewer errors. For example, their timing was on average 10 milliseconds (12%) more accurate in the moving balls task, and they pressed the space bar at the wrong time 25% less in the inhibition task.

Participants’ reaction times were slower during the luteal phase, which begins after ovulation and lasts between 12–14 days up to the beginning of menstruation. They were on average 10–20 milliseconds slower compared to being in any other phase, but their error rate was unchanged.

Dr Flaminia Ronca, first author of the study from UCL Division of Surgery and Interventional Science and ISEH, said: “Research suggests that female athletes are more likely to sustain certain types of sports injuries during the luteal phase and the assumption has been that this is due to biomechanical changes as a result of hormonal variation. But I wasn’t convinced that physical changes alone could explain this association.

“Given that progesterone has an inhibitory effect on the cerebral cortex and oestrogen stimulates it, making us react slower or faster, we wondered if injuries could be a result of a change in athletes’ timing of movements throughout the cycle.

“What is surprising is that the participant’s performance was better when they were on their period, which challenges what women, and perhaps society more generally, assume about their abilities at this particular time of the month.

“I hope that this will provide the basis for positive conversations between coaches and athletes about perceptions and performance: how we feel doesn’t always reflect how we perform.”

To put the findings in context, the authors say the fluctuation in timing could be the difference between an injury or not. Previous research has shown that a variation of just 10 milliseconds can mean the difference between a concussion and a lesser injury, for example. In the colliding balls task, participants’ timing was on average 12 milliseconds slower during the luteal phase compared to every other phase, a difference of 16%.

Dr Megan Lowery, an author of the study from UCL Surgery & Interventional Science and ISEH, said: “There’s lots of anecdotal evidence from women that they might feel clumsy just before ovulation, for example, which is supported by our findings here. My hope is that if women understand how their brains and bodies change during the month, it will help them to adapt.

“Though there’s a lot more research needed in this area, these findings are an important first step towards understanding how women’s cognition affects their athletic performance at different points during their cycle, which will hopefully facilitate positive conversations between coaches and athletes around performance and wellbeing.”

Professor Paul Burgess, senior author of the study from UCL’s Institute of Cognitive Neuroscience, said: “This study emerged from listening carefully to female soccer players and their coaches. We created bespoke cognitive tests to try to mimic the demands made upon the brain at the points in the game where they were telling us that injuries and problems of timing occur at certain times of the menstrual cycle.

“As suggested by what the soccer players had told us, the data suggested that women who menstruate – whether they are athletes or not – do tend to vary in their performance at certain stages of the cycle. As a neuroscientist, I am amazed that we don’t already know more about this, and hope that our study will help motivate increasing interest in this vital aspect of sports medicine.”

Source: University College London

Categories : Injury & Trauma NeurologyTags :

Scarring after Spinal Cord Injury is More Complex than Previously Thought

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Fibrotic scar 14d after spinal cord injury, red – Col1a1+ perivascular fibroblast derived cells Photo: Daniel Holl

New research has found that scar formation after spinal cord injuries is more complex than previously thought. Scientists at Karolinska Institutet have identified two types of perivascular cells as key contributors to scar tissue, which hinders nerve regeneration and functional recovery. These findings, published in Natural Neuroscience, are also relevant for other brain and spinal cord injuries and could lead to targeted therapies for reducing scarring and improving outcomes.

The central nervous system (CNS) has very limited healing abilities. Injuries or autoimmune diseases like multiple sclerosis often lead to permanent functional deficits. 

Regardless of the injury’s cause, the body responds by forming a boundary around the damaged tissue, which eventually becomes permanent scar tissue. 

Two contributing cell types

While scar tissue seals the damaged area, it also prevents functional repair. After spinal cord injuries, scar tissue blocks the regeneration of nerve fibers that connect the brain with the body, resulting in paralysis after severe injuries.

The research team led by Christian Göritz at Karolinska Institutet has made significant progress in understanding how scar tissue forms in the CNS. The group now identified two distinct types of perivascular cells, which line different parts of blood vessels, as the major contributors to fibrotic scar tissue after spinal cord injury. Depending on the lesion’s location, the two identified cell types contribute differently.

“We found that damage to the spinal cord activates perivascular cells close to the damaged area and induces the generation of myofibroblasts, which consequently form persistent scar tissue,” explains first author Daniel Holl, researcher at the Department of Cell and Molecular Biology.

By examining the process of scar formation in detail, the researchers hope to identify specific therapeutic targets to control fibrotic scarring.