Epigenetic regulation by long noncoding RNAs in osteo-/adipogenic differentiation of mesenchymal stromal cells and degenerative bone diseases

Bone is a complex tissue that undergoes constant remodeling to maintain homeostasis,which requires coordinated multilineage differentiation and proper proliferation of mesenchymal stromal cells(MSCs).Mounting evidence indicates that a disturbance of bone homeostasis can trigger degenerative bone diseases,including osteoporosis and osteoarthritis.In addition to conventional genetic modifications,epigenetic modifications(i.e.,DNA methylation,histone modifications,and the expression of noncoding RNAs)are considered to be contributing factors that affect bone homeostasis.Long noncoding RNAs(lncRNAs)were previously regarded as‘transcriptional noise’with no biological functions.However,substantial evidence suggests that lncRNAs have roles in the epigenetic regulation of biological processes in MSCs and related diseases.In this review,we summarized the interactions between lncRNAs and epigenetic modifiers associated with osteo-/adipogenic differentiation of MSCs and the pathogenesis of degenerative bone diseases and highlighted promising lncRNA-based diagnostic and therapeutic targets for bone diseases.

Epigenetic mechanisms involved in developmental nutritional programming

The ways in which epigenetic modifications fix the effects of early environmental events,ensuring sustained responses to transient stimuli,which result in modified gene expression patterns and phenotypes later in life,is a topic of considerable interest.This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics,position and functions of epigenetic marks.Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks,at the global or individual gene level,of environmental stressors in humans and animal models.In parallel,increasing numbers of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes,by highlighting the importance of crosstalk between the different epigenetic marks.A number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition,epigenetic processes and long-term illness.The existence of a self-propagating epigenetic cycle has been demonstrated.Moreover,recent studies demonstrate an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult.Despite recent progress,we are still far from understanding how,when and where environmental stressors disturb key epigenetic mechanisms.Thus,identifying the original key marks and their changes throughout development during an individual's lifetime or over several generations remains a challenging issue.

Human embryonic stem cells as an in vitro model for studying developmental origins of type 2 diabetes

The developmental origins of health and diseases(DOHaD)is a concept stating that adverse intrauterine environments contribute to the health risks of offspring.Since the theory emerged more than 30 years ago,many epidemiological and animal studies have confirmed that in utero exposure to environmental insults,including hyperglycemia and chemicals,increased the risk of developing noncommunicable diseases(NCDs).These NCDs include metabolic syndrome,type 2 diabetes,and complications such as diabetic cardiomyopathy.Studying the effects of different environmental insults on early embryo development would aid in understanding the underlying mechanisms by which these insults promote NCD development.Embryonic stem cells(ESCs)have also been utilized by researchers to study the DOHaD.ESCs have pluripotent characteristics and can be differentiated into almost every cell lineage;therefore,they are excellent in vitro models for studying early developmental events.More importantly,human ESCs(hESCs)are the best alternative to human embryos for research because of ethical concerns.In this review,we will discuss different maternal conditions associated with DOHaD,focusing on the complications of maternal diabetes.Next,we will review the differentiation protocols developed to generate different cell lineages from hESCs.Additionally,we will review how hESCs are utilized as a model for research into the DOHaD.The effects of environmental insults on hESC differentiation and the possible involvement of epigenetic regulation will be discussed.

A Blueberry Extract Supplemented Diet Partially Restores <i>α-Synuclein</i>-Dependent Lifespan Loss and Developmental Defects in Drosophila

Oxidative stress has been strongly associated with Parkinson disease (PD) aetiology. We investigated the effects of blueberry extract (BBE) supplementation on α-synuclein induced phenotypes in a Drosophila melanogaster model of PD. Enhanced α-synuclein expression in D. melanogaster dopaminergic (DA) neurons can reduce lifespan and we have performed longevity assays to measure the effects of BBE on D. melanogaster survival. Flies expressing α-synuclein in their DA neurons fed BBE had up to an 8 day, or 15%, greater median lifespan than those fed a standard control diet. In addition, BBE improved α-synuclein-induced developmental defects in the Drosophila eye. Our biometric analyses revealed that individuals fed BBE had less atypical ommatidia as well as an increased number of mechanosensory bristle cells than those fed a control diet. We propose that BBE, rich in naturally occurring antioxidants, promotes the survival of neurons in tissues with increased levels of α-synuclein through a protective cell survival mechanism.

The essential roles of m^(6)A modification in osteogenesis and common bone diseases

N6-methyladenosine(m^(6)A)is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs.It affects the fate of the modified RNA,including its stability,splicing,and translation,and plays an important role in post-transcriptional regulation.Bones play a key role in supporting and pro-tecting muscles and other organs,facilitating the movement of the organism,ensuring blood production,etc.Bone diseases such as osteoarthritis,osteoporosis,and bone tumors are serious public health problems.The processes of bone development and osteogenic differen-tiation require the precise regulation of gene expression through epigenetic mechanisms including histone,DNA,and RNA modifications.As a reversible dynamic epigenetic mark,m^(6)A modifications affect nearly every important biological process,cellular component,and molecular function,including skeletal development and homeostasis.In recent years,studies have shown that m^(6)A modification is involved in osteogenesis and bone-related diseases.In this review,we summarized the proteins involved in RNA m^(6)A modification and the latest progress in elucidating the regulatory role of m^(6)A modification in bone formation and stem cell direc-tional differentiation.We also discussed the pathological roles and potential molecular mech-anisms of m^(6)A modification in bone-related diseases like osteoporosis and osteosarcoma and suggested potential areas for new strategies that could be used to prevent or treat bone de-fects and bone diseases.

Bone diseases in rabbits with hyperparathyroidism: computed tomography, magnetic resonance imaging and histopathology

Background Hyperparathyroidism （HPT） occurs at an early age and has a high disability rate. Unfortunately, confirmed diagnosis in most patients is done at a very late stage, when the patients have shown typical symptoms and signs, and when treatment does not produce any desirable effect. It has become urgent to find a method that would detect early bone diseases in HPT to obtain time for the ideal treatment. This study evaluated the accuracy of high field magnetic resonance imaging （MRI） combined with spiral computed tomography （SCT） scan in detecting early bone diseases in HPT, through imaging techniques and histopathological examinations on an animal model of HPT. Methods Eighty adult rabbits were randomly divided into two groups with forty in each. The control group was fed normal diet （Ca：P = 1：0.7）; the experimental group was fed high phosphate diet （Ca：P = 1：7） for 3, 4, 5, or 6-month intervals to establish the animal model of HPT. The staging and imaging findings of the early bone diseases in HPT were determined by high field MRI and SCT scan at the 3rd, 4th, 5th and 6th month. Each rabbit was sacrificed after high field MRI and SCT scan, and the parathyroid and bones were removed for pathological examination to evaluate the accuracy of imaging diagnosis. Results Parathyroid histopathological studies revealed hyperplasia, osteoporosis and early cortical bone resorption. The bone diseases in HPT displayed different levels of low signal intensity on T1WI and low to intermediate signal intensity on T2WI in bone of stage 0, Ⅰ, Ⅱ or Ⅲ, but showed correspondingly absent, probable, osteoporotic and subperiosteal cortical resorption on SCT scan. Conclusion High field MRI combined with SCT scan not only detects early bone diseases in HPT, but also indicates staging, and might be a reliable method of studying early bone diseases in HPT.

Sino-UK Symposium on Developmental Biology and Human Diseases Held in Tsinghua

The Sino-UK Symposium on Developmental Biology and Human Diseases opened in Tsinghua May 6, 2006. TheSymposium, which ran through May 8, 2006, was hosted by the Department of Biological Sciences and Biotechnology, Tsinghua University.

Bone alterations in inflammatory bowel diseases

Inflammatory bowel diseases(IBDs)are characterized by a multifactorial partially unknown etiology that involves genetic,immunological and environmental factors.Up to 50%of IBD patients experience at least one extraintestinal manifestation;among them is the involvement of bone density which is referred to as metabolic bone disease(MBD),including osteopenia and osteoporosis.Bone alterations in IBDs population appear to have a multifactorial etiology:Decreased physical activity,inflammation-related bone resorption,multiple intestinal resections,dietary malabsorption of minerals and vitamin D deficiency,genetic factors,gut-bone immune signaling interaction,steroid treatment,microbiota and pathogenic micro-organisms interaction,and dietary malabsorption of minerals,that,all together or individually,may contribute to the alteration of bone mineral density.This review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone fragility.We also want to underline the role of the screening and prophylaxis of bone alterations in Crohn’s disease and ulcerative colitis patients and the importance of treating appropriately MBD.

Roles and regulation of bone morphogenetic protein-7 in kidney development and diseases

The gene encoding bone morphogenetic protein-7(BMP7) is expressed in the developing kidney in embryos and also in the mature organ in adults. During kidney development, expression of BMP7 is essential to determine the final number of nephrons in and proper size of the organ. The secreted BMP7 acts on the nephron progenitor cells to exert its dual functions: To maintain and expand the progenitor population and to provide them with competence to respond to differentiation cues, each relying on distinct signaling pathways. Intriguingly, in the adult organ, BMP7 has been implicated in protection against and regeneration from injury. Exogenous administration of recombinant BMP7 to animal models of kidney diseases has shown promising effects in counteracting inflammation, apoptosis and fibrosis evoked upon injury. Although the expression pattern of BMP7 has been well described, the mechanisms by which it is regulated have remained elusive and the processes by which the secretion sites of BMP7 impinge upon its functions in kidney development and diseases have not yet been assessed. Understanding the regulatory mechanisms will pave the way towards gaining better insight into the roles of BMP7, and to achieving desired control of the gene expression as a therapeutic strategy for kidney diseases.

Clinical benefits of biochemical markers of bone turnover in Egyptian children with chronic liver diseases

AIM： To investigate the association between serum insulin-like growth factor 1 （IGF-1）, osteocalcin, and parathyroid hormone （PTH） levels with the etiology and clinical condition of patients with chronic liver disease. METHODS： Eighty children with hepatocellular damage were divided into 3 groups according to the etiology of disease infection： bilharziasis （9 patients）, hepatitis B virus （HBV, 12 patients） and hepatitis C virus （HCV, 29 patients）. The Child score index was found as A in 24 patients, B in 22 patients, C in 4 patients. Thirty healthy children served as control group.HBsAg, HBcAbIgM, HBcAbIgG, and anti-HCV were detected using ELISA technique. HCV-RNA was measured by reverse transcription polymerase chain reaction （RT-PCR）. Antibllharzial antibodies were detected by indirect haemagglutination test. Liver function tests were performed using autoanalyser. Serum IGF-1, osteocalcin and PTH levels were measured by ELISA technique. Abdominal ultrasonography was also conducted. RESULTS： Serum IGF-1 level was significantly lower in all patient groups with liver diseases, while serum osteocalcin and PTH levels were significantly elevated in patients with HBV and HCV infections compared with the control group. Serum osteocalcin and PTH concentrations were measured with the severity of liver disease from Child A to C. Child A patients unexpectedly showed significantly reduced IGF-1 levels in comparison to patients staged as Child B or C. Serum osteocalcin level was negatively correlated with albumin （14.7 ± 0.54 vs 3.6 ± 0.10, P 〈 0.05）, while that for PTH was positively correlated with total protein （70.1 ± 2.17 vs 6.7 ± 0.10, P 〈 0.05） in patients with HCV infection.

Bone loss in chronic liver diseases:Could healthy liver be a requirement for good bone health?

Given that the liver is involved in many metabolic mechanisms,it is not surprising that chronic liver disease(CLD)could have numerous complications.Secondary osteoporosis and increased bone fragility are frequently overlooked complications in CLD patients.Previous studies implied that up to one-third of these individuals meet diagnostic criteria for osteopenia or osteoporosis.Recent publications indicated that CLD-induced bone fragility depends on the etiology,duration,and stage of liver disease.Therefore,the increased fracture risk in CLD patients puts a severe socioeconomic burden on the health system and urgently requires more effective prevention,diagnosis,and treatment measures.The pathogenesis of CLD-induced bone loss is multifactorial and still insufficiently understood,especially considering the relative impact of increased bone resorption and reduced bone formation in these individuals.It is essential to note that inconsistent findings regarding bone mineral density measurement were previously reported in these individuals.Bone mineral density is widely used as the“golden standard”in the clinical assessment of bone fragility although it is not adequate to predict individual fracture risk.Therefore,microscale bone alterations(bone microstructure,mechanical properties,and cellular indices)were analyzed in CLD individuals.These studies further support the thesis that bone strength could be compromised in CLD individuals,implying that an individualized approach to fracture risk assessment and subsequent therapy is necessary for CLD patients.However,more well-designed studies are required to solve the bone fragility puzzle in CLD patients.

MOFs and bone: Application of MOFs in bone tissue engineering and bone diseases

Metal-organic frameworks(MOFs), a class of hybrid materials, consist of organic linkers and bridging metal ions or clusters. Their tunable pore sizes, large surface area, good biocompatibility, structural variability in combination with materials and chemicals, and osteogenic effects provide potential approaches for bone tissue engineering and bone diseases. And there are more and more research on MOFs in the field of osteogenesis in recent years. This review presents an overall summary of the application in the bone tissue engineering and bone diseases of MOFs and their composites, starting with the synthesis of MOFs, which discusses the advantages and disadvantages of different syntheses. Then, the biological functions of MOFs are discussed, which are the basics of MOFs applied in the organism. Importantly,mechanisms and abundant applications of MOFs are detailed in the bone tissue engineering and bone diseases. Finally, some prospects of MOFs are discussed, for instance, exploring whether MOFs can be used to treat other bone diseases.

Role of fibroblast growth factor receptor 1 in the bone development and skeletal diseases

Accumulating data suggest that FGFs/FGFR1 plays essential roles in the bone development and human skeletal diseases. Conditional inactivation of fgfrl caused different phenotypes displaying in different cells or specific organs and revealed some novel functions of FGFR1 in bone development. Fgfrl mutation mainly induced 2 types of human skeletal diseases, craniosynostosis syndrome and dysplasias. Similar mutation of fgfrl in mouse model just mimicked the phenotype that happened in human. These fa- cilitate the investigation on the underlying mechanism of the diseases. Here we mainly focused on the ad- vance of FGFR1 function in the bone development and its mutation caused skeletal diseases.

An epigenetic view of developmental diseases: new targets, new therapies

Background:Function of epigenetic modifications is one of the most competitive fields in life science.Over the past several decades,it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental diseases.In the present review,we summarize the recent progress about the function of epigenetic regulation,especially DNA and RNA modifi cations in developmental diseases.Data sources:Original research articles and literature reviews published in PubMed-indexed journals.Results:DNA modifications including methylation and demethylation can regulate gene expression,and are involved in development and multiple diseases including Rett syndrome,Autism spectrum disorders,congenital heart disease and cancer,etc.RNA methylation and demethylation play important roles in RNA processing,reprogramming,circadian,and neuronal activity,and then modulate development.Conclusions:DNA and RNA modifications play important roles in development and diseases through regulating gene expression.Epigenetic components could serve as novel targets for the treatment of developmental diseases.

Andrias davidianus bone peptides alleviates hyperuricemia-induced kidney damage in vitro and in vivo

Hyperuricemia(HUA)is a vital risk factor for chronic kidney diseases(CKD)and development of functional foods capable of protecting CKD is of importance.This paper aimed to explore the amelioration effects and mechanism of Andrias davidianus bone peptides(ADBP)on HUA-induced kidney damage.In the present study,we generated the standard ADBP which contained high hydrophobic amino acid and low molecular peptide contents.In vitro results found that ADBP protected uric acid(UA)-induced HK-2 cells from damage by modulating urate transporters and antioxidant defense.In vivo results indicated that ADBP effectively ameliorated renal injury in HUA-induced CKD mice,evidenced by a remarkable decrease in serum UA,creatinine and blood urea nitrogen,improving kidney UA excretion,antioxidant defense and histological kidney deterioration.Metabolomic analysis highlighted 14 metabolites that could be selected as potential biomarkers and attributed to the amelioration effects of ADBP on CKD mice kidney dysfunction.Intriguingly,ADBP restored the gut microbiome homeostasis in CKD mice,especially with respect to the elevated helpful microbial abundance,and the decreased harmful bacterial abundance.This study demonstrated that ADBP displayed great nephroprotective effects,and has great promise as a food or functional food ingredient for the prevention and treatment of HUA-induced CKD.

Report on Cardiovascular Health and Diseases in China 2023:An Updated Summary

Since 1990,China has made considerable progress in resolving the problem of“treatment difficulty”of cardiovascular diseases(CVD).The prevalent unhealthy lifestyle among Chinese residents has exposed a massive proportion of the population to CVD risk factors,and this situation is further worsened due to the accelerated aging population in China.CVD remains one of the greatest threats to the health of Chinese residents.In terms of the proportions of disease mortality among urban and rural residents in China,CVD has persistently ranked first.In 2021,CVD accounted for 48.98%and 47.35%of deaths in rural and urban areas,respectively.Two out of every five deaths can be attributed to CVD.To implement a national policy“focusing on the primary health institute and emphasizing prevention”and truly achieve a shift of CVD prevention and treatment from hospitals to communities,the National Center for Cardiovascular Diseases has organized experts from relevant fields across China to compile the“Report on Cardiovascular Health and Diseases in China”annually since 2005.The 2024 report is established based on representative,published,and high-quality big-data research results from cross-sectional and cohort population epidemiological surveys,randomized controlled clinical trials,large sample registry studies,and typical community prevention and treatment cases,along with data from some projects undertaken by the National Center for Cardiovascular Diseases.These firsthand data not only enrich the content of the current report but also provide a more timely and comprehensive reflection of the status of CVD prevention and treatment in China.

Comprehensive understanding of developmental origins of health and disease concepts: Early intervention to non-communicable diseases in China

Introduction Mortality due to various kinds of noncommunicable diseases (NCDs) has become an increasing focus of attention in recent years.1 With rapidly increasing globalization, lifestyles in low-and middle-income countries increasingly include high-fat diets and inadequate physical exercises are resulting in an increased worldwide burden of NCDs.2,3 A study by the International Diabetes Federation (IDF) showed that about 382 million people had diabetes in 2013, and this will rise to 592 million by 2035.The number of people with type 2 diabetes is increasing in every country, and 80％ of people with diabetes live in low-and middle-income countries.The burden of NCDs and the prevalence of related risk factors such asoverweight and diabetes have also increased in China over the past decades.In 2005, NCDs accounted for an estimated 80％ of deaths and 70％ of disability-adjusted life-years lost in China.

FGF23 associated bone diseases

Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism of FGF23 on phosphate and vitamin D metabolism,and the FGF23 related bone disease.

Advances and perspectives on cellular therapy in acquired bone marrow failure diseases

Acquired bone marrow failure diseases(ABMFD) are a class of hematopoietic stem cell diseases with a commonality of non-inherited disruption of hematopoiesis that results in pancytopenia. ABMFDs also are a group of heterogeneous diseases with different etiologies and treatment options. The three most common ABMFDs are aplastic anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. Stem cell transplantation is the only treatment that can cure these diseases. However, due to high therapy-related mortality, stem cell transplantation has rarely been used as a first line treatment in treating ABMFD. With the advance of personalized medicine and precision medicine, various novel cellular therapy strategies are in trial to increase the efficiency and efficacy of ABMFD treatment. This article aims to review current available stem cell transplantation protocols and promising cellular therapy research in treating ABMFD.

Induction of osteoblast apoptosis stimulates macrophage efferocytosis and paradoxical bone formation

Apoptosis is crucial for tissue homeostasis and organ development.In bone,apoptosis is recognized to be a main fate of osteoblasts,yet the relevance of this process remains underexplored.Using our murine model with inducible Caspase 9,the enzyme that initiates intrinsic apoptosis,we triggered apoptosis in a proportion of mature osteocalcin(OCN^(+))osteoblasts and investigated the impact on postnatal bone development.