Category: Skeletal System

Categories : Paediatrics Skeletal SystemTags :

Newly Discovered Bone Stem Cell Drives Premature Skull Fusion

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Craniosynostosis, the premature fusion of the top of the skull in infants, is caused by an abnormal excess of a previously unknown type of bone-forming stem cell, according to a preclinical study published in Nature.

Occurring in one in 2500 babies, craniosynostosis arises from one of several possible gene mutations. By constricting brain growth, it can lead to abnormal brain development if not corrected surgically. In complex cases, multiple surgeries are needed.

Led by researchers at and led by researchers at Weill Cornell Medicine, the team focused on what happens in the skull of mice with one of the most common mutations found in human craniosynostosis. They found that the mutation drives premature skull fusion by inducing the abnormal proliferation of a type of bone-making stem cell, the DDR2+ stem cell, that had never been described before.

“We can now start to think about treating craniosynostosis not just with surgery but also by blocking this abnormal stem cell activity,” said study co-senior author Dr Matt Greenblatt, an associate professor of pathology and laboratory medicine at Weill Cornell Medicine and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Histology image with stem cells labeled in red and skull region in green

A new stem cell driving disorders of premature skull fusion was transplanted (red), showing that it makes the cartilage seen at sites of skull fusion (green). Credit: Greenblatt lab.

In a study published in Nature in 2018, Dr Greenblatt, study co-senior author Dr Shawon Debnath and their colleagues, described the discovery of a type of bone-forming stem cell they called the CTSK+ stem cell. Because this type of cell is present in the top of the skull, or “calvarium,” in mice, they suspected that it has a role in causing craniosynostosis.

For the new study, they knocked out genes associated with craniosynostosis in CSTK+ stem cells in mice. They expected that the gene deletion somehow would induce these calvarial stem cells to go into bone-making overdrive. This new bone would fuse the flexible, fibrous material called sutures in the skull that normally allow it to expand in infants.

“We were surprised to find that, instead of the mutation in CTSK+ stem cells leading to these stem cells being activated to fuse the bony plates in the skull as we expected, mutations in the CTSK+ stem cells instead led to the depletion of these stem cells at the sutures – and the greater the depletion, the more complete the fusion of the sutures,” Dr Debnath said.

The unexpected finding led the team to hypothesise that another type of bone-forming stem cell was driving the abnormal suture fusion. After further experiments, and a detailed analysis of the cells present at fusing sutures, they identified the culprit: the DDR2+ stem cell, whose daughter cells make bone using a different process than that utilised by CTSK+ cells.

The team found that CTSK+ stem cells normally suppress the production of the DDR2+ stem cells. But the craniosynostosis gene mutation causes the CTSK+ stem cells to die off, allowing the DDR2+ cells to proliferate abnormally.

Collaborating with other researchers, they found the human versions of DDR2+ stem cells and CTSK+ stem cells in calvarial samples from craniosynostosis surgeries—underscoring the likely clinical relevance of their findings in mice.

The findings suggest that inappropriate DDR2+ stem cell proliferation in the calvarium, in infants with craniosynostosis-linked gene mutations, could be treated by suppressing this stem cell population, through mimicking the methods that CTSK+ stem cells normally use to prevent expansion of DDR2+stem cells. The researchers found that the CTSK+ stem cells achieve this suppression by secreting a growth factor protein called IGF-1, and possibly other regulatory proteins.

“We observed that we could partly prevent calvarial fusion by injecting IGF-1 over the calvarium,” said study first author Dr Seoyeon Bok, a postdoctoral researcher in the Greenblatt laboratory.

“I can imagine DDR2+ stem cell-suppressing drug treatments being used along with surgical management, essentially to limit the number of surgeries needed or enhance outcomes,” Dr. Greenblatt said.

In addition to treatment-oriented research, he and his colleagues now are looking for other bone-forming stem cell populations in the skull.

“This work has uncovered much more complexity in the skull than we ever imagined, and we suspect the complexity doesn’t end with these two stem cell types,” Dr Greenblatt said.

Source: Weill Cornell Medicine

Categories : Cancer Skeletal SystemTags :

Why Tumours so Often Metastasise to the Spine

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The vertebral bones that constitute the spine are derived from a distinct type of stem cell that secretes a protein favouring tumour metastases, according to a study led by researchers at Weill Cornell Medicine. The discovery, published in Nature, opens up a new line of research on spinal disorders and helps explain why solid tumours so often spread to the spine, and could lead to new orthopaedic and cancer treatments.

Vertebral bone was found to be derived from a stem cell that is different from other bone-making stem cells. Using bone-like “organoids” made from vertebral stem cells, they showed that the known tendency of tumours to spread to the spine rather than long bones is due largely to a protein called MFGE8, secreted by these stem cells.

“We suspect that many bone diseases preferentially involving the spine are attributable to the distinct properties of vertebral bone stem cells,” said study senior author Dr Matthew Greenblatt.

In recent years, Dr Greenblatt and other scientists have found that different types of bone are derived from different types of bone stem cells. Since vertebrae develop along a different pathway early in life, and also appear to have had a distinct evolutionary trajectory, Dr Greenblatt and his team hypothesised that a distinct vertebral stem cell probably exists.

The researchers started out by isolating what are broadly known as skeletal stem cells, which give rise to all bone and cartilage, from different bones in lab mice based on known surface protein markers of such cells. They then analysed gene activity in these cells to see if they could find a distinct pattern for the ones associated with vertebral bone.

This effort yielded two key findings. The first was a new and more accurate surface-marker-based definition of skeletal stem cells as a whole. This new definition excluded a set of cells that are not stem cells that had been included in the old stem cell definition, thus clouding some prior research in this area.

The second finding was that skeletal stem cells from different bones do indeed vary systematically in their gene activity. From this analysis, the team identified a distinct set of markers for vertebral stem cells, and confirmed these cells’ functional roles to form spinal bone in further experiments in mice and in lab-dish cell culture systems.

The researchers next investigated the phenomenon of the spine’s relative attraction for tumour metastases, including breast, prostate and lung tumours, compared to other types of bone. The traditional theory, dating to the 1940s, is that this “spinal tropism” relates to patterns of blood flow that preferentially convey metastases to the spine versus long bones. But when the researchers reproduced the spinal tropism phenomenon in animal models, they found evidence that blood flow isn’t the explanation, finding instead a clue pointing to vertebral stem cells as the possible culprits.

“We observed that the site of initial seeding of metastatic tumour cells was predominantly in an area of marrow where vertebral stem cells and their progeny cells would be located,” said study first author Dr Jun Sun, a postdoctoral researcher in the Greenblatt laboratory.

Subsequently, the team found that removing vertebral stem cells eliminated the difference in metastasis rates between spine bones and long bones. Ultimately, they determined that MFGE8, a protein secreted in higher amounts by vertebral compared to long bone stem cells, is a major contributor to spinal tropism. To confirm the relevance of the findings in humans, the team collaborated with investigators at Hospital for Special Surgery to identify the human counterparts of the mouse vertebral stem cells and characterise their properties.

The researchers are now exploring methods for blocking MFGE8 to reduce the risk of spinal metastasis in cancer patients. More generally, said Dr Greenblatt, they are studying how the distinctive properties of vertebral stem cells contribute to spinal disorders.

“There’s a subdiscipline in orthopaedics called spinal orthopaedics, and we think that most of the conditions in that clinical category have to do with this stem cell we’ve just identified,” Dr Greenblatt said.

Source: Weill Cornell Medicine

Categories : Ageing Skeletal SystemTags :

Does Low Bone Density Predict an Increased Risk of Dementia?

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People who have low bone density may have an increased risk of developing dementia compared to people who have higher bone density, according to a study of over 3500 people published in Neurology. As an observational study, it only shows an association and cannot prove that low bone density causes dementia.

“Low bone density and dementia are two conditions that commonly affect older people simultaneously, especially as bone loss often increases due to physical inactivity and poor nutrition during dementia,” said study author Mohammad Arfan Ikram, MD, PhD, of the Erasmus University Medical Center in Rotterdam, Netherlands. “However, little is known about bone loss that occurs in the period leading up to dementia. Our study found that bone loss indeed already occurs before dementia and thus is linked to a higher risk of dementia.”

The study involved 3651 people in the Netherlands with an average age of 72 who did not have dementia at the start of the study. Over an average of 11 years of follow-up, 688 people or 19% developed dementia.

X-rays were used to identify bone density, and participants were interviewed every four to five years and completed physical tests such as bone scans and tests for dementia.

Of the 1211 people with the lowest total body bone density, 90 people developed dementia within 10 years, compared to 57 of the 1211 people with the highest bone density.

After adjusting for factors such as age, sex, education, other illnesses and medication use, and a family history of dementia, researchers found that within 10 years, people with the lowest total body bone density were 42% more likely to develop dementia than people in the highest group.

“Previous research has found factors like diet and exercise may impact bones differently as well as the risk of dementia,” Ikram added. “Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss. It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care.”

A limitation of the study is that participants were primarily of European origin and age 70 or older at the start of the study, so these findings may vary in different races, ethnicities, and younger age groups.

Source: American Academy of Neurology

Categories : Ageing Skeletal SystemTags :

Intermittent Corticosteroid Use is Less Likely to Need Fracture Prevention Care

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Prolonged use of corticosteroids, such as prednisolone, has been shown to cause osteoporosis increase fracture risk. The damage can increase the more corticosteroids are taken. But an analysis of prescribing data showed that for those taking intermittent doses of corticosteroids, there was less fracture risk.

Fracture preventive measures are recommended in cases of prolonged corticosteroid use, especially in older age. These can include referrals to specialist osteoporosis clinics or prescribing bisphosphonates.

In a study published in JAMA Dermatology, a team of researchers analysed data to determine whether corticosteroid prescription patterns may affect the likelihood that fracture prevention is considered. The authors, including researchers from the London School of Hygiene & Tropical Medicine (LSHTM), looked at data from across the UK and Ontario, Canada.

Dr Julian Matthewman, lead study author and Research Fellow at LSHTM, said, “Despite well understood benefits of fracture preventive care, including the use of bisphosphonates, previous research suggests that it is under-prescribed. One reason for this could be that doctors are not made aware when some patients have been prescribed an amount of corticosteroids that can damage the bones, such as when they are prescribed gradually or intermittently over multiple prescriptions, potentially even by several doctors.

“In our study, we focused on people aged 66 or older that were prescribed corticosteroids at a level where fracture preventive care should be considered. We used data from GP practices and hospitals across the UK and Ontario, Canada, including information on both corticosteroid and bisphosphonate prescriptions.

“We found that patients prescribed gradual or intermittent corticosteroids were indeed less likely to receive fracture preventive care as compared to patients prescribed corticosteroids in fewer but higher doses or longer-lasting prescriptions. In the UK, the former were about half as likely to receive fracture preventive care. In Ontario, they are about one third less likely.

“Fractures in older age can be dangerous, even deadly, cause disability and incur high costs for health care systems. Hip fractures alone cost the UK around £2 billion, and account for 1.8 million days spent in hospitals each year, according to the Office of Health Improvement & Disparities. Better recognizing patients who can benefit from proactive care has the potential to prevent fractures and their consequences.”

Source: London School of Hygiene & Tropical Medicine

Categories : Lab Tests and Imaging Skeletal SystemTags :

A Quick and Inexpensive Test for Osteoporosis

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In osteoporosis, treatment would be most effective with early detection – something not yet possible with current X-ray based osteoporosis diagnostic tests, which lack the requisite sensitivity. Now, researchers reporting in ACS Central Science have developed a biosensor that could someday help identify those most at risk for osteoporosis using less than a drop of blood.

Early intervention is critical to reducing the morbidity and mortality associated with osteoporosis. The most common technique used to measure changes in bone mineral density (BMD) – dual-energy X-ray absorptiometry – is not sensitive enough to detect BMD loss until a significant amount of damage has already occurred. Several genomic studies, however, have reported genetic variations known as single nucleotide polymorphisms (SNPs) that are associated with increased risk for osteoporosis. Using this information, Ciara K. O’Sullivan and colleagues wanted to develop a portable electrochemical device that would allow them to quickly detect five of these SNPs in finger-prick blood samples in a step toward early diagnosis.

The device involves an electrode array to which DNA fragments for each SNP are attached. When lysed whole blood is applied to the array, any DNA matching the SNPs binds the sequences and is amplified with recombinase polymerase that incorporates ferrocene, a label that facilitates electrochemical detection. Using this platform, the researchers detected osteoporosis-associated SNPs in 15 human blood samples, confirming their results with other methods.

As the DNA does not have to be purified from the blood, the analysis can be performed quickly (about 15 minutes) and inexpensively (< $0.5 per SNP). Furthermore, because the equipment and reagents are readily accessible and portable, the researchers say that the device offers great potential for use at point-of-care settings, rather than being limited to a centralised laboratory. The technology is also versatile and can be readily adapted to detect other SNPs, as the researchers showed previously when identifying drug resistance in Tuberculosis mycobacterium from sputum and cardiomyopathy risk from blood. Although the device does not diagnose osteoporosis itself, it might help physicians identify people whom they should monitor more closely.

Source: Chemical Society

Categories : Implants and Prostheses Skeletal SystemTags :

Understanding Mechanisms Driving Bone Density Loss in Amputee Soldiers

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Combat-related injuries to bone are common in military personnel and can lead to pain and disability. Results from a new study in the Journal of Bone and Mineral Research suggest that amputations for such injuries may negatively affect bone mass.

Traumatic amputation from combat injuries has the potential to lead to osteoporosis through not only systemic inflammation and hormonal changes but also altered loading. Although a documented long-term complication of lower limb amputation is osteoporosis, this is often observed in older less active subjects with comorbidities, thus it is unknown whether this is secondary to systemic changes or changes to the loading environment.

In the study of 575 male adult UK military personnel with combat-related traumatic injuries and 562 without such injuries, veterans who sustained traumatic amputations often had low bone density in the hip region. Changes in bone health appeared to be mechanically driven rather than systemic and were only evident in those with lower limb amputations.

“We hope these results will drive further research into ways to reverse bone mineral density changes,” said co-author Group Captain Alex Bennett, Defence Professor of Rehabilitation, Defence Medical Rehabilitation Centre. “We need to investigate the role of prosthetics and exercise in reversing bone mineral density loss to reduce the longer-term risk of hip fracture. Because systemic treatments like bisphosphonates are not indicated in this young population with bone mineral density loss, it is important to understand other ways to reduce their hip fracture risk.”

Source: Wiley

Categories : Metabolic Disorders Skeletal SystemTags :

Gastric Surgery for Weight Loss Harms Adolescents’ Bone Development

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In sleeve gastrectomy (SG), about 80% of the stomach is removed to reduce obesity and its complications. It has been observed to be associated with bone loss in adolescents, prompting a prospective study published in the Journal of Bone and Mineral Research, that revealed through imaging tests that SG decreases strength and bone mineral density of the lumbar spine in adolescents and young adults.

The researchers followed 29 adolescents and young adults with obesity underwent SG and 30 were without surgery over 12 months. At baseline and 12 months, participants underwent computed tomography of the lumbar spine for bone assessments and magnetic resonance imaging of the abdomen and thigh for body composition assessments.

Participants in the SG group lost an average of 34.3 kg 12 months after surgery, whereas weight was unchanged in controls. There were significant reductions in abdominal fat tissue and thigh muscle in the SG group compared with controls. Also, bone strength and bone mineral density decreased in the SG group compared with controls. Reductions in bone strength and bone mineral density were associated with reductions in body mass index, abdominal fat tissue, and muscle.

“Weight loss surgery is very effective in treating obesity and obesity-associated comorbidities in adolescents and young adults with obesity; however, it can cause loss of bone density and strength. We hope that our study raises awareness of the importance of bone health after weight loss surgery, so physicians can make sure that children eat a healthy diet with enough calcium and vitamin D and engage in weight-bearing activity to build up muscle mass, which is good for bones,” said corresponding author Miriam A. Bredella, MD, of Massachusetts General Hospital. 

Source: Wiley

Categories : Ageing Skeletal SystemTags :

Flipping the Switch on Osteoporosis with Epigenetic Discovery

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Van Andel Institute scientists have pinpointed a key driver of low bone density, a discovery that may lead to improved treatments with fewer side effects for women with osteoporosis. Their findings appear in the journal Science Advances.

Their research reveals that loss of an epigenetic modulator, KDM5C, preserves bone mass in mice. KDM5C works by altering epigenetic ‘marks’, switches that ensure the instructions written in DNA are read in the right time and place.

Several medications are approved to treat osteoporosis but fears of rare, severe side effects often are a barrier for their use. Treatments that leverage the hormone oestrogen also are available, but are only recommended for low-dose, short-term use due in part to associations with cancer risk.

It is well-established that women experience disproportionately lower bone mass than men throughout their lives. Loss of bone mass accelerates with menopause, increasing the risk of osteoporosis and associated fractures for women as they age.

To figure out why this happens, VAI Associate Professors Connie M. Krawczyk, PhD, and Tao Yang, PhD, and their teams looked at the differences in the ways bone is regulated in male and female mice, which share many similarities with humans and are important models for studying health and disease. They focused on osteoclasts, which help maintain bone health by breaking down and recycling old bone.

“Osteoporosis is a common disease that can have debilitating outcomes,” Yang said. “KDM5C is a promising target to treat low bone mass in women because it is highly specific. We’re hopeful that our findings will contribute to improved therapies.”

The researchers found reducing KDM5C disrupted cellular energy production in osteoclasts, which slowed down the recycling process and preserved bone mass. Importantly, KDM5C is linked to X chromosomes, which means it is more active in females than in males.

“Lowering KDM5C levels is like flipping a switch to stop an overactive recycling process. The result is more bone mass, which ultimately means stronger bones,” Krawczyk said. “We’re very excited about this work and look forward to carrying out future studies to refine our findings. At the end of the day, we hope these insights make a difference for people with osteoporosis.”

Source: Van Andel Research Institute

Categories : Skeletal SystemTags :

Changes in Hyaluronic Acid Properties Drive Osteoarthritis

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Source: CC0

The composition of synovial fluid changes significantly in osteoarthritis: The concentration and molecular weight of hyaluronic acid tends to decrease and is commonly used to diagnose the disease. An international group of researchers explored the disease-driven breakdown of hyaluronan and the mechanistic implications of these changes on the lubrication and subsequent wear of joints.

“One of the most important properties of the synovial fluid is its viscosity,” said Rosa Maria Espinosa-Marzal, co-author of the study published in the journal Biointerphases. “Viscosity is a measure of the internal frictional force between adjacent layers of a fluid in relative motion, or, more simply, a fluid’s resistance to flow. Large, high molecular weight polymers such as hyaluronic acid play a significant role in maintaining a high viscosity of the synovial fluid, which helps maintain a fluid film and reduces friction between articulating surfaces during motion.”

Through analysis with neutron and light scattering, the team determined that the structure of the lipid-hyaluronic-acid complexes in the bulk solution is a function of concentration and its molecular weight.

The researchers found the hyaluronic acid’s concentration and molecular weight both play a role in how the lubricant reacts with different surfaces.

“Our results show low molecular weight hyaluronic acid, which mimics osteoarthritis-diseased joints, hinders the adsorption of the hyaluronic-acid-lipid complex,” said Espinosa-Marzal, of the University of Illinois Urbana-Champaign. “The lack of the formation of an amorphous film on the surface may reflect a consequence of osteoarthritis, since this film should help reduce friction and wear.”

Their hypothesis is that this film’s absence may increase wear of the cartilage surface. In contrast, high molecular weight hyaluronic-acid-lipid complexes form an amorphous film, which presumably helps maintain the mechanical integrity and longevity of efficient lubrication in healthy cartilage.

Studies on hyaluronic acid itself and hyaluronic-acid-lipid complexes “do not entirely support hyaluronic acid’s role in providing high lubricity to the cartilage’s articular surface, which is still a bit controversial,” Espinosa-Marzal said. “Our results indicate that for low molecular weight hyaluronic acid, this is likely the case.”

By exploring the complex interplay between phospholipid and hyaluronic acid self-assembly, and the role of molecular weight on surface affinity, “our study illuminates a mechanism whereby the ‘vicious circle’ of osteoarthritis can be explained,” said co-author Mark Rutland, from KTH Royal Institute of Technology.

Source: American Institute of Physics

Categories : Genetics Skeletal SystemTags :

Scientists Close in on the Genetic Determinants of Height

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Human height is dictated by the sealing of the growth plates at the ends of bones that harden as a child develops. Along with diet and disease, heritability has long been known to be a factor determining height. Now, researchers report in Cell Genomics that cells in these plates determine the length and shape of bones and may partly predict final stature. The study identified potential “height genes” and found that genetic changes affecting cartilage cell maturation may strongly influence adult height.

“The study is really understanding the genetics of skeleton,” says paediatric endocrinologist and senior author Nora Renthal of Boston Children’s Hospital and Harvard University. “Height is a good starting point to understand the relationship between genes, growth plates, and skeletal growth because we can measure the height of every human being.”

To pinpoint height-associated genes, the team screened 600 million mouse cartilage cells to identify genes that, when deleted, can alter cell growth and maturation. These types of cellular changes in the growth plate are known to lead to variations in human height. The search turned up 145 genes mostly linked to skeletal disorders and are crucial for growth plate maturation and bone formation.

The team then compared these genes with data from genome-wide association studies (GWAS) of human height, which located “hotspots” along the entire human genome where “height genes” are located. But these regions can contain multiple genes, making it hard for researchers to track down and study an individual target.

“That’s kind of like looking for your friend’s house, but you only know the zip code,” says Renthal. “It’s difficult.”

The comparison revealed that genes affecting cartilage cells overlap with hotspots from human height GWAS, precisely locating genes in our DNA that likely play a role in determining our stature. Renthal and her team also discovered that many of the GWAS suggested height genes led to early maturation in cartilage cells. These findings suggest that genetic changes affecting cartilage cell maturation may influence height more.

Renthal notes that studies in mouse cells may not fully translate to humans, and GWAS are observational studies that cannot fully illustrate the cause and effects of height. But her study provides a novel method to bridge the two methods and provide new insights into human genetics.

Next, the team plans to use the method to understand hormones’ effect on cartilage cells. They will also look into some of the 145 genes that have no known connection to skeletal growth. The investigation may reveal new genes and pathways that play a role in the bones.

“I see patients with skeletal dysplasia, where there isn’t any treatment because genetics made their bones grow this way,” says Renthal. “It’s my hope that the more we can understand about the biology of the growth plate, the more we would be able to intervene at earlier times in growing skeletons and the life of a kid.”

Source: MedicalXpress