Tag Archives: #osteoporosis

Osteoporosis Affects Men, Too (Medicine)

Worldwide, 1 in 3 women over age 50 will experience a bone fracture due to osteoporosis, according to the International Osteoporosis Foundation. But it’s not just women, as 1 in 5 men over age 50 also will have the same issue.

Reporter Jason Howland explains in the Mayo Clinic Minute.

Watch: The Mayo Clinic Minute

Journalists: Broadcast-quality video pkg (1:00) is in the downloads at the end of the post.
Please “Courtesy: Mayo Clinic News Network.” Read the script.

Osteoporosis is thinning of your bones to the point where they can break.

“Bone loss really starts to occur in a big way at about age 55,” says Dr. Bart Clarke, a Mayo Clinic endocrinologist.

Dr. Clarke is medical editor of Mayo Clinic Guide to Preventing and Treating Osteoporosis. He says women are most at risk, especially those past menopause, when bone loss is accelerated because of a lack of estrogen. But women aren’t the only people affected.

“About 20 percent of the patients in the country who have osteoporosis are men,” says Dr. Clarke.

Without a bone density test, most people won’t even know they have osteoporosis because there are usually no symptoms until a bone is broken …

“… which is one of the reasons why this is dangerous,” says Dr. Clarke. “Because it’s like having high blood pressure or high blood sugar. Many times, you have no clue because nobody’s checked.”

If you’re in your 50s, Dr. Clarke recommends talking to your primary care provider and asking about bone density testing if you have had previous low-trauma fractures or risk factors for osteoporosis. You also should maintain good nutrition with proper amounts of calcium and vitamin D, and stay physically active.

Featured image credit: Mayo Clinic


Provided by Mayo Clinic

Optimized Vitamin K2 Helps to Treat Osteoporosis (Chemistry)

Osteoporosis is a common debilitating bone disease, which is characterized by bone loss and degeneration of bone structure, primarily caused by an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts. When bone resorption exceeds bone formation, it will lead to low bone density and increase the risk of fractures, leading to osteoporosis.

Recently, a research group led by Prof. ZHENG Zhiming from the Institute of Intelligent Machines of the Hefei Institutes of Physical Science (HFIPS) made progress in the study of vitamin K2 to improve bone health, introducing a new solution to treat osteoporosis.

As a coenzyme of glutamate γ-carboxylase, Vitamin K2 can carboxylate the glutamate residues of vitamin K-dependent protein-osteocalcin and matrix γ-carboxylated glutamate residue proteins. The osteocalcin would promote bone formation. However, fat-soluble vitamin K2 is difficult to reach its peak concentration in the body. Besides, there is a risk of local overdose as it’s stored in the liver.

“Our work is to improve the bioavailability of vitamin K2,” said TANG Hengfang, a student who joined the research, “this time, we used amphiphilic carrier protein to modified vitamin K2 hydrophilically.”

Detection of markers related to osteoblast differentiation (Image by TANG Hengfang)
 

The result was striking. They obtained spherical nanoparticles uniformly dispersed in the aqueous solution by optimizing the mixing molar ratio of carrier protein and vitamin K2 (MK7).

“We applied the vitamin K2 nanoparticles to MC3T3-E1 cells,” said TANG, “and found that the expressions of osteoblastic markers were significantly upregulated, including alkaline phosphatase (ALP), osteocalcin and OPG/RANKL.” The formation of extracellular mineralized nodules was also significantly strengthened, indicating that the vitamin K2 nanoparticles could effectively promote osteoblastic differentiation.

The research results opened new possibilities for osteoporosis with vitamin K2 as alternative.

This research has been supported by the National Key R&D Program of China, the Key research and development program of Anhui Province and other projects.

Featured image: Schematic diagram of carrier protein hydrophilic modification of vitamin K2 and promotion of osteoblast differentiation (Image by TANG Hengfang)


Reference: Tang, H., Zhu, Z., Zheng, Z. et al. A study of hydrophobins-modified menaquinone-7 on osteoblastic cells differentiation. Mol Cell Biochem 476, 1939–1948 (2021). https://doi.org/10.1007/s11010-021-04062-z


Provided by Chinese Academy of Sciences

New Type of Bone Cell Could Reveal Targets For Osteoporosis Treatment (Medicine)

The discovery of a new type of bone cell may uncover therapeutic targets for a range of skeletal diseases.

Researchers at the Garvan Institute of Medical Research have discovered a new type of bone cell that may reveal new therapeutic approaches for osteoporosis and other skeletal diseases.

The new cells, which the researchers term ‘osteomorphs’, are found in the blood and bone marrow, and fuse together to form osteoclasts, specialised cells that break down bone tissue. They have a unique genomic profile that reveals promising and as yet unexplored targets for therapy.

“This discovery is a game-changer, which not only helps us understand bone biology but presents significant new in-roads for osteoporosis therapy,” says co-senior author Professor Tri Phan, who heads the Intravital Microscopy and Gene Expression Lab at the Garvan Institute. “Osteomorphs express several genes that seem to be linked to bone disease, which could lead scientists to entirely new ways to target osteoporosis.”

The discovery is published today in the prestigious journal Cell.

Bone resorption under the microscope

At a microscopic level, our skeleton is constantly changing. To support bone growth, maintenance and repair damage, specialised cells on the bone surface break down old bone tissue (known as bone resorption) and build it back up. A change to that balance can lead to bone fragility, including osteoporosis, which is estimated to affect over 900,000 people in Australia alone.

To better understand bone resorption and how to treat it, the Garvan researchers investigated osteoclasts, the cells that are specialised in resorbing bone, in an experimental model. Using intravital imaging technology that allows a deep look inside living bone tissue, the researchers noticed that osteoclasts did something unusual – they split up into smaller cells, and then joined back to form osteoclasts again.

“This process was completely new to us. The consensus until now has been that osteoclasts undergo cell death after they’ve done their job, but we saw they were recycling by splitting up and joining back together again, a process which we hypothesise may increase their lifespan,” says Dr Michelle McDonald, first author of the paper and leader of the Bone Microenvironment Group at Garvan.

“We also found these cells in the blood and bone marrow, suggesting they can travel to other parts of the skeleton, as a likely ‘reserve’ of cells that are ready to fuse and deploy when osteoclasts are needed again.”

A unique genetic signature

Using cutting-edge single cell RNA sequencing technology, which the researchers developed specifically for studying these cells in bone, the team found that the new cells switched on a number of genes.

“The profile of genes that were switched on in these cells was really interesting – while many genes were also expressed by osteoclasts, several were unique. This, together with the evidence of the new re-fusion processes observed by intravital imaging, convinced us that we had discovered a new cell type, which we called osteomorphs, after the Mighty Morphin Power Rangers,” says author Dr Weng Hua Khoo.

With colleagues at Imperial College London, the researchers deleted 40 of the genes switched on in osteomorphs in experimental models. They found that for 17 of these genes, the deletion impacted on the amount of bone and bone strength, indicating a critical role in controlling bone.

“When we further investigated human genomic data in publicly available databases, we found that genes switched on in osteomorphs were linked to human gene variants that lead to skeletal dysplasia and control bone mineral density,” says co-senior author Professor Peter Croucher, Deputy Director of the Garvan Institute and head of the Bone Biology Lab.

“Together, these findings revealed just how crucial osteomorphs are in bone maintenance, and that understanding these cells and the genes that control them may reveal new therapeutic targets for skeletal disease.”

Explaining a common side effect

Beyond revealing new avenues for treatment, the team’s findings provide a possible explanation of a commonly observed clinical phenomenon.

“Some individuals who discontinue the osteoporosis treatment denosumab experience a reduction in bone mass and an increase in so-called ‘rebound vertebral fractures’,” explains Professor Phan.

The authors say that denosumab blocks a molecule that they found is needed for the osteomorphs to form osteoclasts. They suspect that patients who receive denosumab accumulate osteomorphs in their body, and that these are released to form osteoclasts, which resorb bone, when treatment is stopped. 

The researchers say studying the effects of denosumab and other osteoporosis medication on osteomorphs may inform how those treatments could be improved and how their withdrawal effects could be prevented.

“While we don’t yet fully understand the role of osteomorphs, their existence has already led to a major step change in our understanding of the skeleton,” says Professor Croucher. “This research has been an enormous combined international effort across many scientific disciplines. We look forward to exploring how these cells may change the approach to osteoporosis and other skeletal diseases moving forward.”

This research was supported by Mrs Janice Gibson and the Ernest Heine Family Foundation, a Cancer Institute NSW Career Development Fellowship, a Future Fellowship from the Australian Research Council, Fellowships from the National Health and Medical Research Council of Australia (NHMRC) and a Wellcome Trust Strategic Award (101123), an American Society of Bone and Mineral Research Rising Star Award, and a UNSW Cellular Genomics Futures Institute grant.

Collaborating researchers are from the University of Western Australia, University of Queensland, Imperial College London, UNSW Sydney, the Australian National University, the Centenary Institute, the University of Sydney, Medical University of Vienna, CSIRO, Biovinc and the University of Bristol.

Featured image: Study authors (L-R) Dr Weng Hua Khoo, Professor Tri Phan, Professor Peter Croucher, Dr Michelle Mcdonald © GIMR


Reference: Michelle M. Mcdonald, Weng Hua Khoo, Pei Ying Ng et al., “Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption”, 2021. DOI: https://doi.org/10.1016/j.cell.2021.02.002


Provided by Garvan Institute of Medical Research

Unlocking the Mystery Behind Skeletal Aging (Medicine)

By identifying the underlying factors leading to bone loss and osteoporosis, UCLA dentist-scientists hope to pave the way to new treatments

Researchers from the UCLA School of Dentistry have identified the role a critical enzyme plays in skeletal aging and bone loss, putting them one step closer to understanding the complex biological mechanisms that lead to osteoporosis, the bone disease that afflicts some 200 million people worldwide.

The findings from their study in mice, published online today in the journal Cell Stem Cell, could hold an important key to developing more effective treatments for osteoporosis and improving the lives of an aging population, they say.

Cells in the bone marrow known as mesenchymal stem cells serve as the building blocks of the body’s skeletal tissues, but whether these stem cells ultimately develop into bone or fat tissues is controlled in part by what are known as epigenetic factors — molecules that regulate genes, silencing some and activating others.

The UCLA researchers, led by distinguished professor Dr. Cun-Yu Wang, chair of oral biology at the dentistry school, demonstrated that when the epigenetic factor KDM4B is absent from mesenchymal stem cells, these cells are far more likely to differentiate into fat cells than bone cells, resulting in an unhealthy imbalance that exacerbates skeletal aging and leads to brittle bones and fractures over time.

“We know that bone loss comes with age, but the mechanisms behind extreme cases such as osteoporosis have, up until recently, been very vague,” said Dr. Wang, the study’s corresponding author and the Dr. No-Hee Park Professor of Dentistry at UCLA. “In this study, we built on more than seven years of research managed by my postdoctoral scholar and lead author Dr. Peng Deng in the hope that we can eventually prevent skeletal aging and osteoporosis.”

While scientists have long understood the cellular pathway involved in bone tissue formation, the role of epigenetic factors has been murkier. Previous research by Wang, Deng and others had identified that the enzyme KDM4B plays an important epigenetic role in bone formation, but they were unsure of how its absence might affect the processes of bone formation and bone loss.

To test this, the research team created a mouse model in which KDM4B was absent or removed in several different scenarios. They found that the removal of the enzyme pushed mesenchymal stem cells to create more fat instead of bone tissue, leading to bone loss over time, which mimics skeletal aging.

In one important scenario, the scientists examined stem cell senescence, or deterioration and exhaustion — the natural process by which mesenchymal stem cells stop rejuvenating or creating more of themselves over time. The team unexpectedly found that senescence, which leads to natural skeletal aging, was characterized by a loss of KDM4B.

A loss of the epigenic factor KDM4B promotes the accumulation fat cells in the bone marrow (pictured here) of aging mice, researchers found. © Peng Deng/UCLA School of Dentistry

In addition to age, other environmental factors are thought to reduce bone quality and exacerbate bone loss, including a high-fat diet. The team demonstrated that a loss of KDM4B significantly promoted bone loss and the accumulation of marrow fat in mice placed on a high-fat diet.

Finally, the team showed that parathyroid hormone, an anabolic drug approved by the U.S. Food and Drug Administration for the treatment of aging-related bone loss, helps to maintain the pool of mesenchymal stem cells in aging mice in a KDM4B-dependent manner.

The results not only confirm the critical role KDM4B plays in mesenchymal stem cell fate decision, skeletal aging and osteoporosis, but they show that the loss of KDM4B exacerbates bone loss under a number of conditions and, surprisingly, that KDM4B controls the ability of mesenchymal stem cells to self-renew. This study is the first in vivo research to demonstrate that the loss of an epigenetic factor promotes adult stem cell deterioration and exhaustion in skeletal aging.

The findings, the researchers say, hold promise for the eventual development of strategies to reverse bone-fat imbalance, as well as for new prevention and treatment methods that address skeletal aging and osteoporosis by rejuvenating adult stem cells.

“The work of Dr. Wang, his lab members and collaborators provides new molecular insight into the changes associated with skeletal aging,” said Dr. Paul Krebsbach, dean of the UCLA School of Dentistry. “These findings are an important step towards what may lead to more effective treatment for the millions of people who suffer from bone loss and osteoporosis.”

The work was supported by grants from the National Institute of Dental and Craniofacial Research (part of the National Institutes of Health), the UCLA Clinical and Translational Science Institute and the Hsien Family Foundation charitable funds.

Dr. Wang is also a member of the UCLA Jonsson Comprehensive Cancer Center, the UCLA Samueli School of Engineering and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Additional authors include Dr. Peng Deng, Quan Yuan, Yingduan Cheng, Jiong Li, Zhenqing Liu, Yan Liu, Mari Ekimyan Salvo and Ye Li, all of the Laboratory of Molecular Signaling at the UCLA School of Dentistry; Trent Su of the UCLA Department of Biological Chemistry; Jing Wang, Weiguang Wang, Guoping Fan and Karen Lyons of the David Geffen School of Medicine at UCLA; and Dr. Bo Yu of the division of constitutive and regenerative science at the UCLA School of Dentistry.

Featured image: Epigenetic factors like the enzyme KDM4B play a major role in the aging-related bone loss that leads to brittle bones and fractures, researchers say. © UCLA Health


Reference: Peng Deng, Quan Yuan, Yingduan Cheng et al., “Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging”, Cell Stem Cell, 2021. DOI: https://doi.org/10.1016/j.stem.2021.01.010


Provided by UCLA Health

Discovery of ‘Adolescent’ Skeletal Stem Cells Might Someday Help Prevent Osteoporosis (Biology)

A new study reported in STEM CELLS reveals a unique population of skeletal stem cells (SSCs) that function during the transitional period between rapid bone growth and bone maintenance. This discovery provides an opportunity to determine whether alterations in the SSCs’ pattern might affect bone formation, as well as helps us understand the physiological factors that regulate its timing.

Diana L. Carlone, Ph.D., of Boston Children’s Hospital and the Harvard Stem Cell Institute. © AlphaMed Press

“This is particularly important given that anything that interferes with the proper development of bone mass during childhood and adolescence has long-lasting effects on our health, including the development of osteoporosis in adults,” said corresponding author Diana L. Carlone, Ph.D., of Boston Children’s Hospital and the Harvard Stem Cell Institute.

The researchers came across this new information while investigating the role of mTert-expressing cells in postnatal mouse long bone. Postnatal bone formation relies on skeletal progenitor/stem cells. These cells also play a key role in repairing fractured or otherwise damaged bone. Tert (telomerase) is an enzyme found in the body’s cells that helps keep cells alive by adding DNA to the ends of their chromosomes (telomeres). Each time a cell divides, its telomeres lose a small amount of DNA and become shorter. Tert activity prevents this aging process.

Recent lineage-tracing data indicate that SSC populations are regulated by time and spacing, with distinct populations functioning during bone growth and maintenance. In addition, growth-associated SSCs have been suggested as the predecessors to adult SSCs, implying that the SSC populations are highly complex and perhaps exist in hierarchies. There is strong interest in identifying stem cells within the skeleton, and much has been done to understand these cells in vitro (“in the test tube”); however, these findings are tempered by the fact that the lineage potential of cells in vitro can differ from their capacity in vivo (in the body).

“Going forward it will be imperative that markers and the cell populations they identify are validated in vivo before being accepted as an SSC population,” Dr. Carlone said.

Previously, she and her team had shown that mTert expression marks embryonic stem cells, induced pluripotent stem cells and self-renewing tissue stem cells. Other researchers had proven that telomerase is necessary for SSC self-renewal and differentiation, and that a decline in telomerase activity in humans correlates with a decrease in bone homeostasis (stability), leading to osteoporosis. While all these studies indicate that telomerase is important for SSC function and bone homeostasis, what remained unclear was whether telomerase expression marks skeletal stem cells.

That’s what the Carlone team set out to discover. They already knew that discrete SSC populations function during specific time periods corresponding to rapid bone growth and bone maintenance. To investigate whether mTert is expressed during these same periods, the Carlone team examined the long bones of an mTert mouse model they had developed, which recapitulates endogenous telomerase activity, specifically looking at what was happening at one, three and 12 weeks of age. To do this, they used quantitative (q) RT-PCR analysis (reverse transcription-polymerase chain reaction), which is the most sensitive technique for mRNA detection and quantitation currently available.

What they learned is that although mTert was detected at low levels during the multiple time points, it was upregulated at the age of weaning (three weeks), suggesting that mTert+ cells are temporally regulated and mark a discrete time period interposed between rapid bone growth and bone maintenance. They next looked at the location of the mTert-expressing cells at these same endpoints and were able to identify the mTert+ cells in regions known to house SSCs, including the fibrous tissue at the ends of long bones (the metaphyseal stroma), as well as in the growth plate and the bone marrow.

“We also show that mTert-expressing cells are a distinct SSC population with enriched colony-forming capacity and contribute to multiple mesenchymal lineages in vitro. In contrast, in vivo lineage-tracing studies identified mTert+ cells as osteochondral progenitors and contribute to the bone-forming cell pool during endochondral bone growth, with a subset persisting into adulthood,” Dr. Carlone noted.

“Taken together, our results show that mTert expression is temporally regulated and marks SSCs during a discrete phase of transitional growth between rapid bone growth and maintenance that corresponds to the adolescent growth spurt in humans. We believe this warrants future studies focused on understanding how alterations in this cell population during this growth period translate into disorders such as osteoporosis.”

“The temporal regulation of telomerase in the progenitor cells that form bone during adolescent growth is a very important advance in the understanding of bone development,” said Dr. Jan Nolta, Editor-in-Chief of STEM CELLS. “This knowledge could also aid in understanding and improving regenerative therapies for bone injury and disease.”

The full article, “Telomerase expression marks transitional growth-associated skeletal progenitor/stem cells,” can be accessed at https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/stem.3318.

Provided by AlphaMed Press

About the Journal: STEM CELLS, a peer reviewed journal published monthly, provides a forum for prompt publication of original investigative papers and concise reviews. The journal covers all aspects of stem cells: embryonic stem cells/induced pluripotent stem cells; tissue-specific stem cells; cancer stem cells; the stem cell niche; stem cell epigenetics, genomics and proteomics; and translational and clinical research. STEM CELLS is co-published by AlphaMed Press and Wiley.

About AlphaMed Press: Established in 1983, AlphaMed Press with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes three internationally renowned peer-reviewed journals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines. STEM CELLS® is the world’s first journal devoted to this fast paced field of research. THE ONCOLOGIST® is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. STEM CELLS TRANSLATIONAL MEDICINE® is dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices.

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To Understand Periodontal Disease, Researchers Examine the Surprising Behavior of T Cells (Medicine)

In diseases characterized by bone loss—such as periodontitis, rheumatoid arthritis, and osteoporosis—there is a lot that scientists still don’t understand. What is the role of the immune response in the process? What happens to the regulatory mechanisms that protect bone?

In a paper published recently in Scientific Reports, researchers from the Forsyth Institute and the Universidad de Chile describe a mechanism that unlocks a piece of the puzzle. Looking at periodontal disease in a mouse model, scientists found that a specific type of T cell, known as regulatory T cells, start behaving in unexpected ways. These cells lose their ability to regulate bone loss and instead begin promoting inflammation.

“That is important because in many therapies analyzed in in-vivo models, researchers usually check if the number of regulatory T cells has increased. But they should check if these cells are indeed functioning,” says Dr. Carla Alvarez, a postdoctoral researcher at Forsyth and lead author of the paper.

Regulatory T cells control the body’s immune response. In periodontal disease, bone loss occurs because the body’s immune system responds disproportionately to the microbial threat, causing inflammation and destroying healthy tissue. Normally, regulatory T cells help suppress that destruction, but they appear to lose their suppressive abilities during periodontal disease.

This process is analyzed in the field of osteoimmunology, which explores the complex interactions between the immune system and bone metabolism.

“This is an interesting mechanism highlighting how bone loss is taking place in periodontal disease,” says Dr. Alpdogan Kantarci, Senior Member of Staff at Forsyth and co-author of the paper together with Dr. Rolando Vernal, Professor from the School of Dentistry at Universidad de Chile.

In the case of periodontal disease, a potential therapy targeting regulatory T cells could restore the T cells’ normal functioning, not just increase their numbers.

“Unfortunately, this is not a linear process—that’s the complicated part,” Kantarci says.

Periodontal disease is initiated by microbes in the mouth, making it all the more complex.

“The relationship between immune response and bone is not so straightforward,” says Alvarez. “There are multiple components. You have to imagine a complex network of signaling and cells that participate.” This cellular and microbial complexity is what makes the disease so difficult to study in humans. However, examining this mechanism in humans is the next step of the research, Alvarez says. The research team is planning a collaborative study to look at healthy and diseased patients, intending to observe similar mechanisms to what was seen in the animal model.

Reference: Alvarez, C., Suliman, S., Almarhoumi, R. et al. Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci Rep 10, 19018 (2020). https://www.nature.com/articles/s41598-020-76038-w https://doi.org/10.1038/s41598-020-76038-w

Provided by Forsyth

Long-term Study Finds Dozens of New Genetic Markers Associated with Lifetime Bone Growth (Medicine)

Findings suggest that risk of fractures occurring in later life could be identified in childhood and may lead to tailored interventions.

A multidisciplinary team of researchers led by Children’s Hospital of Philadelphia (CHOP) has discovered several genetic markers associated with bone mineral accrual, which could ultimately help identify causes of eventual osteoporosis earlier in life through genetic testing. The findings, which were made possible by following a group of children over several years, were published online by the journal Genome Biology.

Osteoporosis is widely considered a disease of old age. However, the accrual of bone density early in life is critical for achieving optimal bone mass in adulthood and influences bone health throughout a person’s life. While studies have looked at genetic markers associated with bone health in adulthood, very few have been performed in children during the most critical period of bone growth.

Additionally, genome-wide association studies (GWAS) have attempted to pinpoint genetic markers associated with bone growth, but an improved understanding of the spatial organization of the human genome can reveal underlying causal genes that may have otherwise been missed.

“We wanted to do a GWAS study that measured bone mineral accrual at multiple time points to provide us with proper longitudinal data at ages when the skeleton is growing and developing,” said Struan F.A. Grant, PhD, Director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Endowed Chair for Diabetes Research at CHOP and lead author of the study. “By doing a longitudinal study, we had much greater power in a relatively small cohort of patients.”

The study team, which included experts in genetics as well as bone biology, compiled data from approximately 11,000 bone density measurements that were conducted as part of the Bone Mineral Density in Childhood Study (BMDCS), a project headed by Babette S. Zemel, PhD, Associate Program Director of the Clinical and Translational Research Center, Director of the Bionutrition Core Laboratory at CHOP and first author of the study. Once the genetic markers were identified, the researchers used a variant-to-gene mapping method to look for both underlying causal variants as well as corresponding effector genes. They further investigated specific genetic markers, or loci, to characterize their impact on osteoblast function.

Using this method, the researchers identified 40 distinct loci – including 35 that had not been previously reported – associated with bone accrual. Several of these loci are associated with fracture risk later in life. Additionally, the researchers identified two novel effector genes that are potentially causative. Finally, they also identified multiple genetic pathways involved in variation in bone accrual that have important roles in determining whether cells eventually become osteoblasts (bone cells) or adipocytes (fat cells).

“This study is one of many that demonstrates how these loci are manifesting themselves earlier in life than we had previously thought,” said Zemel. “In this case, our findings may help us better tailor lifestyle interventions, such as exercise and dietary changes, that will help patients later in life, and they may also lead to novel therapeutic interventions.”

This research was supported by R01 HD58886, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts (N01-HD-1-3228, -3329, -3330, -3331, -3332, -3333), the CTSA program Grant 8 UL1 TR000077, NIH/NICHD grant 1K99HD099330-01, NIH/NHLBI grant K01HL123612, the Daniel B. Burke Endowed Chair for Diabetes Research, R01 HD10040, and R01 HG010067. The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.

Reference: Cousminer, D.L., Wagley, Y., Pippin, J.A. et al. Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual. Genome Biol 22, 1 (2021). https://doi.org/10.1186/s13059-020-02207-9 https://genomebiology.biomedcentral.com/articles/10.1186/s13059-020-02207-9

Provided by Children’s Hospital of Philadelphia

About Children’s Hospital of Philadelphia: Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

New Drug Form May Help Treat Osteoporosis, Calcium-related Disorders (Medicine)

A novel form of a drug used to treat osteoporosis that comes with the potential for fewer side effects may provide a new option for patients.

Elizabeth Topp, a Purdue professor of physical and industrial pharmacy, helped develop a stabilized form of human calcitonin, which is a peptide drug already used for people with osteoporosis. © Chris Adam/Purdue University

The work is supported by the National Institutes of Health and is published in Biophysical Journal.

Purdue University innovators developed a stabilized form of human calcitonin, which is a peptide drug already used for people with osteoporosis. Researchers at Purdue created a prodrug form of the peptide hormone to increase its effectiveness as an osteoporosis treatment.

In humans, calcitonin is the hormone responsible for normal calcium homeostasis. When prescribed to osteoporosis patients, calcitonin inhibits bone resorption, resulting in increased bone mass.

Unfortunately, human calcitonin undergoes fibrillation in aqueous solution, leading to reduced efficacy when used as a therapeutic. As a substitute, osteoporosis patients are prescribed salmon calcitonin. It does not fibrillate as rapidly but suffers from low potency and the potential for several adverse side effects.

“The technology can help make these calcitonin drugs safer and more effective,” said Elizabeth Topp, a Purdue professor of physical and industrial pharmacy. “Our approach will increase the therapeutic potential of human calcitonin, promising a more effective option to replace salmon calcitonin for osteoporosis and related disorders.”

To decrease the fibrillation propensity and increase the therapeutic benefit of human calcitonin, Purdue researchers phosphorylated specific amino acid residues.

“Many promising new peptide drugs tend to form fibrils,” Topp said. “This technology provides a way to stabilize them in a reversible way so that the stabilizing modification comes off when the drug is given to the patient.”

Provided by Purdue University

Researchers Identify A Rare Genetic Bone Disorder Through Massive Sequencing Methods (Medicine)

They have used precision medicine to uncover and treat new skeletal disorders.

Researchers of the “Cell Biology and Physiology-LABRET” group of the University of Malaga (UMA), together with the Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), have described a new genetic skeletal disorder based on a precision medicine strategy.

Alteration of focal points revealing cell signaling problems in patients with skeletal dysplasia caused by mutations in LAMA5. Green represents immunofluorescence localization of Vinculin (focal adhesions), purple is Phalloidin (actin cytoskeleton) and blue represents nuclei. © University of Malaga

By using methods of massive sequencing -of all genes- they have identified the mutations that caused a rare bone disorder, particularly, the mutations in “LAMA5”, the gene encoding an extracellular matrix protein around blood vessels in skeletal tissue.

This disorder consists in an extreme bone fragility combined with a lack of mineralization and skeletal deformity associated with joint dislocation and heart diseases, as well as a pulmonary insufficiency that causes perinatal mortality -at the time of birth.

The study was carried out at the Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), in collaboration with the International Skeletal Dysplasia Registry of the University of California (Los Angeles), where the sequencing of affected patients’ genes was conducted. The Masaryk University (Czech Republic) also participated in the study.

“Our scientific team has been researching rare genetic syndromes affecting the skeleton for years, with a view to find a medical solution for patients with complicated diagnosis and treatment”, explains the researcher of the Department of Cell Biology, Iván Durán, main author of the study, which findings have been published in the scientific journal EBIOMEDICiNE.

According to this expert, precision medicine is the key to uncovering the genetic and molecular factors that produce this type of pathologies, and hence understanding the mechanism that causes them, enabling the development of tailored therapies.

Therefore, the researchers of the UMA have also described the mechanism of disease by generating cell models based on gene editing, simulating the mutations in LAMA5 in order to confirm if these mutations are the cause and determine the molecular process that triggers the problem. These cell models were developed by gene editing with CRISPR, introducing mutations causing a null or hypomorphic gene.

New mechanism of disease

“Thanks to these models we uncovered a new signaling pathway governing the skeleton formation -that makes the bone grow and stay healthy-, which means that our work has not only revealed a new disease, but also an unknown mechanism that could be used for common bone conditions”, says Durán.

As he clarifies, the presence of LAMA5 among cells involved in the skeleton formation indicates, therefore, that the appearance of signals from special blood vessels could be a highly effective means of bone repair and regeneration.

“Not only do blood vessels provide irrigation to bones, but also convey signals and support niches for stem cells that can be mobilized to induce a regenerative process. It seems that LAMA5 is a key component to support pericyte-like stem cells”, he clarifies.

New osteogenic biomaterial

Osteoporosis and osteogenesis imperfecta are diseases that cause bone fragility and affect a significant percentage of the population. Besides, these pathologies often present bone defects that are very difficult to repair. These scientific breakthrough will facilitate the design of new treatments and strategies for all types of bone fragility conditions.

In this sense, the “Cell Biology and Physiology” group of the UMA, which also belongs to the Biomedical Research Institute of Malaga (IBIMA), along with CIBER-BBN and the Cell Therapy Network, progress on a new project to develop an osteogenic biomaterial that would heal complex fractures in individuals with bone fragility and a low capacity of bone regeneration.

Reference: Barad M, Csukasi F, Kunova-Bosakova M, Martin J, Zhang W, Taylor SP, Dix P, Lachman R, Zieba J, Bamshad M, Nickerson D, Chong JX, Cohn DH, Krejci P, Krakow D, Duran I. Mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia. 2020 EBioMedicine. Nov 23;62:103075. doi: 10.1016/j.ebiom.2020.103075

Provided by University of Malaga