Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and ...Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk.We revealed the immune landscape of BM in non-BML and BML,and the transition to pro-inflammatory states of clusters in BMLs,such as classical monocytes and nonclassical monocytes.Non-classical monocytes have high inflammation,OA gene signatures,and senescence scores,and are potential primary clusters promoting OA progression.Histological signs of OA related to the cellular landscape in damaged cartilage were identified,including PreFC exhaustion.The BM-cartilage crosstalk at the cell-cell interaction(CCIs)level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage,and PreFC is one of the primary receivers of the signal.We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice,compared with classical monocyte and PreFC,respectively.Transcription factor 7 like 2(TCF7L2)was identified as a shared transcription factor in the senescence of monocytes and chondrocytes,facilitating the development of the senescence-associated secretory phenotype(SASP).Therefore,senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML–cartilage crosstalk in OA,with TCF7L2 serving as a regulator.展开更多
Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apo...Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis.The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA.As age advances,mitochondrial function declines progressively,which leads to an imbalance in chondrocyte energy homeostasis,partially initiating the process of cartilage degeneration.Elevated oxidative stress,impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology,with mitochondrial DNA haplogroups,particularly haplogroup J,influencing OA progression.Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases,with triphenylphosphonium(TPP)emerging as the most widely utilized molecule.Other strategies encompass Dequalinium(DQA),the Szeto-Schiller(SS)tetrapeptide family,the KLA peptide,and mitochondrial-penetrating peptides(MPP),etc.展开更多
Abnormal accumulation of collagen fibrils is a hallmark feature of oral submucous fibrosis(OSF).However,the precise characteristics and underlying mechanisms remain unclear,impeding the advancement of potential therap...Abnormal accumulation of collagen fibrils is a hallmark feature of oral submucous fibrosis(OSF).However,the precise characteristics and underlying mechanisms remain unclear,impeding the advancement of potential therapeutic approaches.Here,we observed that collagen Ⅰ,the main component of the extracellular matrix,first accumulated in the lamina propria and subsequently in the submucosa of OSF specimens as the disease progressed.Using RNA-seq and Immunofluorescence in OSF specimens,we screened the cartilage oligomeric matrix protein(COMP)responsible for the abnormal collagen accumulation.Genetic COMP deficiency reduced arecoline-stimulated collagen I deposition significantly in vivo.In comparison,both COMP and collagen Ⅰ were upregulated under arecoline stimulation in wild-type mice.Human oral buccal mucosal fibroblasts(hBMFs)also exhibited increased secretion of COMP and collagen I after stimulation in vitro.COMP knockdown in hBMFs downregulates arecoline-stimulated collagen Ⅰ secretion.We further demonstrated that hBMFs present heterogeneous responses to arecoline stimulation,of which COMP-positive fibroblasts secrete more collagen Ⅰ.Since COMP is a molecular bridge with Fibril-associated collagens with Interrupted Triple helices(FACIT)in the collagen network,we further screened and identified collagen XIV,a FACIT member,co-localizing with both COMP and collagen Ⅰ.Collagen XIV expression increased under arecoline stimulation in wild-type mice,whereas it was hardly expressed in the Comp^(-/-) mice,even with under stimulation.In summary,we found that COMP may mediates abnormal collagen Ⅰ deposition by functions with collagen XIV during the progression of OSF,suggesting its potential to be targeted in treating OSF.展开更多
BACKGROUND The Turkish Delight technique,initially described by Erol in 2000,involves the use of diced cartilage wrapped in oxidized cellulose(Surgicel^(TM))for nasal grafting in secondary rhinoplasty.CASE SUMMARY Thi...BACKGROUND The Turkish Delight technique,initially described by Erol in 2000,involves the use of diced cartilage wrapped in oxidized cellulose(Surgicel^(TM))for nasal grafting in secondary rhinoplasty.CASE SUMMARY This paper presents a novel adaptation called Diced Cartilage in Capsula,where diced cartilage is wrapped in the periprosthetic capsule material formed from a previous breast augmentation procedure instead of fascia,a technique based on the Diced Cartilage in Fascia method.Utilizing autologous,biocompatible material minimizes foreign body reactions and enhances graft integration.This innovative approach demonstrates the potential for specific practices in cosmetic surgery by optimizing patient-specific resources and improving surgical outcomes.CONCLUSION The report compares traditional Turkish Delight applications with this new method,discussing biocompatibility,technique efficacy,and benefits in rhinoplasty.展开更多
Cartilage,as a specialized connective tissue,underpins joint mobility and mech-anical load distribution while exhibiting inherently limited self-repair capabilities.This comprehensive review redefines the current land...Cartilage,as a specialized connective tissue,underpins joint mobility and mech-anical load distribution while exhibiting inherently limited self-repair capabilities.This comprehensive review redefines the current landscape of cartilage imaging by exploring conventional and advanced modalities used to assess both the structural and biochemical attributes of cartilage.Whereas conventional radio-graphy and ultrasound offer rudimentary,indirect assessments,cutting-edge techniques-including magnetic resonance imaging(MRI)-based sequences such as T2 mapping,delayed gadolinium-enhanced MRI of cartilage,and sodium MRI-enable early detection of molecular alterations in the cartilage matrix.In ad-dition,hybrid approaches like positron emission tomography-MRI are emerging to provide integrative molecular and structural insights.This article critically appraises imaging strategies in the context of regenerative interventions,high-lighting technical innovations,persistent challenges,and future directions to facilitate improved diagnostic accuracy and therapeutic monitoring.展开更多
Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,i...Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,including bone and cartilage metabolism.Deletion of the core clock gene Bmal1 leads to pathological bone alterations,while the phenotypes are not consistent.Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism,but the exact regulatory mechanisms remain unclear.This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism,the upstream regulatory factors that control Bmal1,and the current Bmal1 knockout mouse models for research.We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.展开更多
Purpose:This study aimed to assess the influence of older vs.younger age and previous anterior cruciate ligament(ACL)injury on resting serum cartilage oligomeric matrix protein(sCOMP(t_(pre)))concentration,on immediat...Purpose:This study aimed to assess the influence of older vs.younger age and previous anterior cruciate ligament(ACL)injury on resting serum cartilage oligomeric matrix protein(sCOMP(t_(pre)))concentration,on immediate load-induced sCOMP kinetics after a 30-min treadmill walking stress(ΔsCOMP(t_(post))),and on the dose-response relationship between ambulatory load magnitude andΔsCOMP(t_(post)).Methods:A total of 85 participants were recruited in 4 groups(20-30 years:24 healthy,23 ACL-injured;40-60 years:23 healthy,15 ACL-injured).Blood samples were collected immediately before and after a walking stress at 80%,100%,or 120%bodyweight(BW)on 3 test days and analyzed for sCOMP concentration.Linear models were used to estimate the effect of age,knee status(unilateral ACL injury,2-10 years prior),and sex on sCOMP(t_(pre)),ΔsCOMP(t_(post)),and the dose-re sponse between ambulatory load magnitude andΔsCOMP(t_(post)).Results:We found that sCOMP(t_(pre))was 21%higher in older than younger participants(p<0.001)but did not differ between ACL-injured and healthy participants(p=0.632).Also,ΔsCOMP(t_(post))was 19%lower in older than younger participants(p=0.030)and increased with body mass index(p<0.001),sCOMP(t_(pre))(p=0.008),and with 120%BW(p<0.001),independent of age,ACL injury,or sex.Conclusion:Age but not prior ACL injury influences resting sCOMP and load-induced sCOMP.The dose-response relationship between ambulatory load magnitude and load-induced sCOMP changes is not affected by age,ACL injury,or sex.A better understanding of systemic sCOMP and the role of its mechanoresponse for the understanding of osteoarthritis pathophysiology and monitoring intervention efficacy may require knowledge of individual cartilage composition and tissue-level loading parameters.展开更多
Repairing and regenerating cartilage defects in osteoarthritis patients remains challenging.Traditional treatments primarily offer symptom relief without addressing the underlying progression of the disease.Stem cell ...Repairing and regenerating cartilage defects in osteoarthritis patients remains challenging.Traditional treatments primarily offer symptom relief without addressing the underlying progression of the disease.Stem cell therapies provide a promising solution,yet they face limitations such as short retention times,low survival rates in vivo,and insufficient extracellular matrix(ECM)production.Stem cell-based hydrogel therapy offers a controlled microenvironment that can mitigate these challenges and enhance cell therapy effectiveness.This review evaluates the advantages and limitations of various stem cell types and hydrogel materials,summarizing recent advances in their combination for cartilage repair.The potential of stem cell-hydrogel therapies is highlighted,along with the remaining challenges and future directions for improving their clinical application.展开更多
Mitochondria are vital organelles whose impairment leads to numerous metabolic disorders.Mitochondrial transplantation serves as a promising clinical therapy.However,its widespread application is hindered by the limit...Mitochondria are vital organelles whose impairment leads to numerous metabolic disorders.Mitochondrial transplantation serves as a promising clinical therapy.However,its widespread application is hindered by the limited availability of healthy mitochondria,with the dose required reaching up to 109 mitochondria per injection/patient.This necessitates sustainable and tractable approaches for producing high-quality human mitochondria.In this study,we demonstrated a highly efficient mitochondriaproducing strategy by manipulating mitobiogenesis and tuning organelle balance in human mesenchymal stem cells(MSCs).Utilizing an optimized culture medium(mito-condition)developed from our established formula,we achieved an 854-fold increase in mitochondria production compared to normal MSC culture within 15 days.These mitochondria were not only significantly expanded but also exhibited superior function both before and after isolation,with ATP production levels reaching 5.71 times that of normal mitochondria.Mechanistically,we revealed activation of the AMPK pathway and the establishment of a novel cellular state ideal for mitochondrial fabrication,characterized by enhanced proliferation and mitobiogenesis while suppressing other energy-consuming activities.Furthermore,the in vivo function of these mitochondria was validated in the mitotherapy in a mouse osteoarthritis model,resulting in significant cartilage regeneration over a 12-week period.Overall,this study presented a new strategy for the off-the-shelf fabrication of human mitochondria and provided insights into the molecular mechanisms governing organelle synthesis.展开更多
Osteoarthritis is a common aging-related disorder that is confined mostly to the chondral layer of joints(e.g., the knee) but can spread to bony layers over time. In its early stages, osteoarthritis has minimal sympto...Osteoarthritis is a common aging-related disorder that is confined mostly to the chondral layer of joints(e.g., the knee) but can spread to bony layers over time. In its early stages, osteoarthritis has minimal symptoms;however, these gradually worsen over time and include joint pain, stiffness, loss of mobility, and inflammation. The exposed subchondral bone of a Grade 4 osteoarthritic knee is highly prone to erosion if left untreated due to persistent rubbing between the bones, which can lead to painful bone spurs. However, treating osteoarthritis is especially challenging due to the poor mitotic potential and low metabolic activity of chondrocytes. Although currently available tissue-engineered products(e.g., BST-CarGel■, TruFit■, and Atelocollagen■) can achieve structural reconstruction and tissue regeneration, final clinical outcomes can still be improved. Major challenges faced during clinical studies of tissue-engineered constructs include chondrocyte hypertrophy and the development of mechanically inferior fibrous tissue, among others. These issues can be addressed by selecting suitable biomaterial combinations, mimicking the three-dimensional(3D) architecture of the tissue matrix, and better controlling inflammation. Furthermore, it is crucial to generate essential signaling molecules within the articular cartilage ecosystem. This approach must also account for the microarchitecture of the affected joint and support the chondrogenic differentiation of mesenchymal stem cells. The use of tissue-engineered constructs has the potential to overcome each of these challenges, since materials can be modified for drug/biomolecule delivery while simultaneously facilitating the regeneration of robust articular cartilage. Three-dimensional printing has been successfully used in tissue engineering to achieve bioprinting. By manipulating conventional 3D printing techniques and the types of bioink used, many different types of bioprinting have emerged. Overall, these bioprinting techniques can be used to address various challenges associated with osteoarthritis treatment.展开更多
The SH2 domain-containing protein tyrosine phosphatase 2(SHP2,also known as PTP2C),encoded by PTPN11,is ubiquitously expressed and has context-specific effects.It promotes RAS/MAPK signaling downstream of receptor tyr...The SH2 domain-containing protein tyrosine phosphatase 2(SHP2,also known as PTP2C),encoded by PTPN11,is ubiquitously expressed and has context-specific effects.It promotes RAS/MAPK signaling downstream of receptor tyrosine kinases,cytokine receptors,and extracellular matrix proteins,and was shown in various lineages to modulate cell survival,proliferation,differentiation,and migration.Over the past decade,PTPN11 inactivation in chondrocytes was found to cause metachondromatosis,a rare disorder characterized by multiple enchondromas and osteochondroma-like lesions.Moreover,SHP2 inhibition was found to mitigate osteoarthritis pathogenesis in mice,and abundant but incomplete evidence suggests that SHP2 is crucial for cartilage development and adult homeostasis,during which its expression and activity are tightly regulated transcriptionally and posttranslationally,and by varying sets of functional partners.Fully uncovering SHP2 actions and regulation in chondrocytes is thus fundamental to understanding the mechanisms underlying both rare and common cartilage diseases and to designing effective disease treatments.We here review current knowledge,highlight recent discoveries and controversies,and propose new research directions to answer remaining questions.展开更多
The treatment of prolonged inflammation and cartilage damage due to osteoarthritis(OA)is a major clinical challenge.We developed a comprehensive cartilage repair therapy using a dual drug-loaded nanocomposite hydrogel...The treatment of prolonged inflammation and cartilage damage due to osteoarthritis(OA)is a major clinical challenge.We developed a comprehensive cartilage repair therapy using a dual drug-loaded nanocomposite hydrogel that leveraged the spatiotemporal immunomodulatory effects of a naturally degradable protein-based nanocomposite hydrogel.The hydrogel acted as a scaffold that created a favorable microenvironment for cartilage regeneration.The hydrogel recruited macrophages and human mesenchymal stem cells(hMSCs),which supported the growth and adhesion of osteoblasts,and degraded to provide nutrition.Silk protein nanoparticles were chemically cross-linked with kartogenin,and humanlike collagen was physically cross-linked with dexamethasone through hydrogen bonding.In the early stages of cartilage repair,a large quantity of dexamethasone was released.The dexamethasone acted as an anti-inflammatory agent and a spatiotemporal modulator of the polarization of M1 macrophages into M2 macrophages.In the middle and late stages of cartilage repair,kartogenin underwent sustained release from the hydrogel,inducing the differentiation of hMSCs into chondrocytes and maintaining chondrocyte stability.Therefore,kartogenin and dexamethasone acted synergistically to induce cartilage repair.In conclusion,we developed an integrated therapeutic system by constructing a cartilage regeneration microenvironment and inducing synergistic drug-based cartilage regeneration.The therapeutic system demonstrated satisfactory efficacy for repairing cartilage damage in rabbits.展开更多
GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte ...GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.展开更多
Articular cartilage damage caused by trauma or degenerative diseases such as osteoarthritis remains a major therapeutic challenge due to the tissue’s limited regenerative capacity.Traditional surgical interventions-i...Articular cartilage damage caused by trauma or degenerative diseases such as osteoarthritis remains a major therapeutic challenge due to the tissue’s limited regenerative capacity.Traditional surgical interventions-including microfracture,autologous chondrocyte implantation,and osteochondral grafting-often result in the formation of biomechanically inferior fibrocartilage and fail to restore longterm joint function.In contrast,stem cell-based strategies have emerged as a promising approach for regenerating hyaline-like cartilage by combining the biological potential of mesenchymal stem cells and induced pluripotent stem cells with advances in tissue engineering.This review synthesizes the current understanding of cartilage structure and repair limitations,evaluates the regenerative potential of various stem cell sources,and highlights engineering innovations such as bioactive scaffolds,controlled growth factor delivery,and threedimensional bioprinting.We also examine key preclinical studies and early-phase clinical trials demonstrating the safety and efficacy of stem cell-based therapies.Finally,we explore future directions,including gene editing,exosome-based therapeutics,and personalized regenerative strategies,that may address remaining translational barriers.Collectively,stem cell-centered approaches offer a transformative avenue toward durable,functional cartilage repair and hold strong potential for clinical application.展开更多
Bisphenol A(BPA)is a recognized estrogenic endocrine disruptor that poses a threat to the reproductive health of fish.However,it remains unclear whether and how paternal BPA exposure can lead to developmental toxicity...Bisphenol A(BPA)is a recognized estrogenic endocrine disruptor that poses a threat to the reproductive health of fish.However,it remains unclear whether and how paternal BPA exposure can lead to developmental toxicity in offspring.To explore the potential paternal BPA exposure impacts on craniofacial cartilage growth in offspring,male rare minnows were subjected to BPA and subsequently mated with normal females to produce progeny.Our results demonstrated that paternal BPA exposure resulted in increased malformation and delayed craniofacial cartilage development in the F1 offspring.Furthermore,BPA exposure led to differential expression of 28 miRNAs in paternal sperm in F0 generation(13 upregulated and 15 downregulated),among which 7 miRNAs were involved in the regulation of bone development.BPA also downregulated the expression of bmp2a and Runx1 during F1 embryonic development.The inhibited bmp2a expression might derive from BPA's stimulation of one miRNA,aca-miR-16a-5P,due to bmp2a being one of its target genes.Notably,paternal BPA exposure did not affect craniofacial cartilage development or gonadal development in the F2 generation.Overall,our study sheds light on the molecular mechanisms underlying the impact of paternal BPA exposure on facial chondrogenesis in offspring and provides theoretical support for the ecological protection of fish populations.展开更多
Abnormal biomechanics plays a central role in the development of knee osteoarthritis(KOA).Low-intensity laser therapy(LILT)is considered an applicable method for the treatment of osteoarthritis.Current research on LIL...Abnormal biomechanics plays a central role in the development of knee osteoarthritis(KOA).Low-intensity laser therapy(LILT)is considered an applicable method for the treatment of osteoarthritis.Current research on LILT for the treatment of KOA has focused on the regeneration of articular cartilage.Its biomechanical changes in periarticular tissues have been less well studied,and its role in improving abnormal joint biomechanics is unclear.This study aimed to investigate the role of LILT in improving the biomechanical properties of muscle and cartilage in KOA joints to alleviate cartilage degradation.In this study,a semiconductor laser with a wavelength of 808 nm was used to perform laser interventions in a KOA rat model 3 days per week for 6 weeks.The results of muscle stretch tests showed that LILT could significantly reduce the modulus of elasticity of KOA soleus muscle.Hematoxylin and eosin staining showed that LILT significantly increased the cross-sectional area of the soleus muscle fibers.This suggests that LILT alleviated KOA-induced soleus muscle atrophy and restored the mechanical properties of the muscle tissue.The results of compressive elastic modulus and electrical impedance characterization of cartilage showed that laser intervention significantly increased the elastic modulus and resistivity of cartilage.Results from safranin o-fast green staining and immunohistochemistry showed that LILT significantly increased the synthesis of type II collagen in the cartilage matrix.This may be one of the potential mechanisms by which LILT improves the mechanical properties of cartilage.In addition,immunohistochemistry also showed that LILT reduced the expression of matrix metallo-proteinase-13 in cartilage and effectively inhibited the degradation of the cartilage matrix in KOA.In conclusion,the present study demonstrated that LILT alleviated the abnormal biomechanics of KOA joint tissues by improving the mechanical properties of joint muscles and cartilage,thereby slowing down the degradation of KOA cartilage.展开更多
BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and ...BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.展开更多
Clinical translation of tissue-engineered advanced therapeutic medicinal products is hindered by a lack of patient-dependent and independent in-process biological quality controls that are reflective of in vivo outcom...Clinical translation of tissue-engineered advanced therapeutic medicinal products is hindered by a lack of patient-dependent and independent in-process biological quality controls that are reflective of in vivo outcomes.Recent insights into the mechanism of native bone repair highlight a robust path dependence.Organoid-based bottom-up developmental engineering mimics this pathdependence to design personalized living implants scaffold-free,with in-build outcome predictability.Yet,adequate(noninvasive)quality metrics of engineered tissues are lacking.Moreover,insufficient insight into the role of donor variability and biological sex as influencing factors for the mechanism toward bone repair hinders the implementation of such protocols for personalized bone implants.Here,male and female bone-forming organoids were compared to non-bone-forming organoids regarding their extracellular matrix composition,transcriptome,and secreted proteome signatures to directly link in vivo outcomes to quality metrics.As a result,donor variability in bone-forming callus organoids pointed towards two distinct pathways to bone,through either a hypertrophic cartilage or a fibrocartilaginous template.The followed pathway was determined early,as a biological sexdependent activation of distinct progenitor populations.Independent of donor or biological sex,a cartilage-to-bone transition was driven by a common panel of secreted factors that played a role in extracellular matrix remodeling,mineralization,and attraction of vasculature.Hence,the secreted proteome is a source of noninvasive biomarkers that report on biological potency and could be the missing link toward data-driven decision-making in organoid-based bone tissue engineering.展开更多
The primary objective of Cartilage Tissue Engineering(CTE)involves repairing or rebuilding impaired cartilage in an effort to restore joint functionality and enhance patients'quality of life.In this field,research...The primary objective of Cartilage Tissue Engineering(CTE)involves repairing or rebuilding impaired cartilage in an effort to restore joint functionality and enhance patients'quality of life.In this field,researchers are constantly exploring new materials and technologies to address the challenges posed by cartilage damage.Biomimetic hydrogels present several distinct advantages in articular cartilage repair when compared to conventional treatment methods like minimally invasive surgery,joint replacement,and drug therapies.These hydrogels effectively mimic the mechanical characteristics of natural cartilage while also promoting cell adhesion,proliferation,and differentiation through the inclusion of bioactive factors.This results in the creation of high-performance biomaterials,positioning them as a particularly promising therapeutic option.Recently,researchers have drawn inspiration from the intricate structures found in soft tissues to develop various types of biomimetic hydrogels.These innovative hydrogels find applications across various fields,such as biomedicine,tissue engineering,and flexible electronics.In tissue engineering,these materials serve as optimal scaffolds for cartilage regeneration and aid in restoring tissue function.Nevertheless,creating and manufacturing biomimetic hydrogels with complex designs,strong mechanical properties,and multifunctionality poses significant challenges.This paper reviews existing studies on natural and synthetic matrices for biomimetic hydrogels,explores the similarities between these hydrogels and natural cartilage,examines their biological and physical characteristics,discusses their advantages and limitations,and suggests future research avenues.展开更多
BACKGROUND Osteoarthritis(OA)remains a challenging degenerative joint disease with limited therapeutic interventions.AIM To investigate the potential of synovial mesenchymal stem cell(SMSC)-derived exosomes(SMSCs-Exos...BACKGROUND Osteoarthritis(OA)remains a challenging degenerative joint disease with limited therapeutic interventions.AIM To investigate the potential of synovial mesenchymal stem cell(SMSC)-derived exosomes(SMSCs-Exos)delivering GrpE-like 1(GRPEL1)in promoting cartilage repair through phosphatase and tensin homolog-induced putative kinase 1(PINK1)-mediated mitophagy activation.METHODS A comprehensive research approach was employed,including bioinformatics analysis of gene expression datasets(GSE169077 and GSE114007),in vitro ex-periments with CHON-001 chondrocytes,and in vivo rat knee OA models.Experi-mental techniques encompassed gene expression profiling,immunofluorescence staining,western blot analysis,co-immunoprecipitation,cell proliferation and migration assays,and histological examinations.Exosomes were genetically modified to overexpress or knockdown GRPEL1,and their effects on cellular function and mitochondrial dynamics were systematically evaluated.RESULTS Bioinformatics analysis revealed GRPEL1 as a critical mitophagy-related gene with significantly altered expression in OA.In vitro studies demonstrated that GRPEL1-loaded SMSCs-Exos effectively counteracted interleukin-1 beta-induced cellular damage by enhancing chondrocyte proliferation and migration,preserving extracellular matrix integrity.Mechanistic investigations confirmed direct interaction between GRPEL1 and PINK1,leading to enhanced mitophagy activation.In vivo rat models substantiated these findings,showing significantly reduced cartilage damage,restored proteoglycan content,and improved joint structure in groups receiving GRPEL1-overexpressing exosomes.Key molecular changes included decreased reactive oxygen species,improved mitochondrial membrane potential,and increased mitophagy markers.CONCLUSION This study provides compelling evidence that SMSCs-Exos delivering GRPEL1 can effectively activate PINK1-mediated mitophagy,offering a promising therapeutic strategy for cartilage repair in OA.The research unveils a novel molecular mechanism for targeting mitochondrial dysfunction and presents a potential disease-modifying approach beyond current symptomatic treatments.展开更多
基金supported by the Nature Science Foundation of Zhejiang Province(grant no.LD22C060002)National Science Foundation of China(grant no.82274547,82474240)+2 种基金Zhejiang Provincial Medical and Health Science and Technology Fund(grant no.2024KY1223)Research Project of Zhejiang Chinese Medical University(grant no.2023JKZKTS34)Project of Chunyan Special Fund for Chinese Medicine Development of Zhejiang Chinese Medical University(grant no.CY202305)。
文摘Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk.We revealed the immune landscape of BM in non-BML and BML,and the transition to pro-inflammatory states of clusters in BMLs,such as classical monocytes and nonclassical monocytes.Non-classical monocytes have high inflammation,OA gene signatures,and senescence scores,and are potential primary clusters promoting OA progression.Histological signs of OA related to the cellular landscape in damaged cartilage were identified,including PreFC exhaustion.The BM-cartilage crosstalk at the cell-cell interaction(CCIs)level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage,and PreFC is one of the primary receivers of the signal.We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice,compared with classical monocyte and PreFC,respectively.Transcription factor 7 like 2(TCF7L2)was identified as a shared transcription factor in the senescence of monocytes and chondrocytes,facilitating the development of the senescence-associated secretory phenotype(SASP).Therefore,senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML–cartilage crosstalk in OA,with TCF7L2 serving as a regulator.
基金supported by the Science and Technology Program of Guangzhou(202206010140)the Guangdong Provincial Key Research and Development Program(2023B1111050003).
文摘Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis.The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA.As age advances,mitochondrial function declines progressively,which leads to an imbalance in chondrocyte energy homeostasis,partially initiating the process of cartilage degeneration.Elevated oxidative stress,impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology,with mitochondrial DNA haplogroups,particularly haplogroup J,influencing OA progression.Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases,with triphenylphosphonium(TPP)emerging as the most widely utilized molecule.Other strategies encompass Dequalinium(DQA),the Szeto-Schiller(SS)tetrapeptide family,the KLA peptide,and mitochondrial-penetrating peptides(MPP),etc.
基金supported by the National Natural Science Foundation of China grant(81974150).
文摘Abnormal accumulation of collagen fibrils is a hallmark feature of oral submucous fibrosis(OSF).However,the precise characteristics and underlying mechanisms remain unclear,impeding the advancement of potential therapeutic approaches.Here,we observed that collagen Ⅰ,the main component of the extracellular matrix,first accumulated in the lamina propria and subsequently in the submucosa of OSF specimens as the disease progressed.Using RNA-seq and Immunofluorescence in OSF specimens,we screened the cartilage oligomeric matrix protein(COMP)responsible for the abnormal collagen accumulation.Genetic COMP deficiency reduced arecoline-stimulated collagen I deposition significantly in vivo.In comparison,both COMP and collagen Ⅰ were upregulated under arecoline stimulation in wild-type mice.Human oral buccal mucosal fibroblasts(hBMFs)also exhibited increased secretion of COMP and collagen I after stimulation in vitro.COMP knockdown in hBMFs downregulates arecoline-stimulated collagen Ⅰ secretion.We further demonstrated that hBMFs present heterogeneous responses to arecoline stimulation,of which COMP-positive fibroblasts secrete more collagen Ⅰ.Since COMP is a molecular bridge with Fibril-associated collagens with Interrupted Triple helices(FACIT)in the collagen network,we further screened and identified collagen XIV,a FACIT member,co-localizing with both COMP and collagen Ⅰ.Collagen XIV expression increased under arecoline stimulation in wild-type mice,whereas it was hardly expressed in the Comp^(-/-) mice,even with under stimulation.In summary,we found that COMP may mediates abnormal collagen Ⅰ deposition by functions with collagen XIV during the progression of OSF,suggesting its potential to be targeted in treating OSF.
文摘BACKGROUND The Turkish Delight technique,initially described by Erol in 2000,involves the use of diced cartilage wrapped in oxidized cellulose(Surgicel^(TM))for nasal grafting in secondary rhinoplasty.CASE SUMMARY This paper presents a novel adaptation called Diced Cartilage in Capsula,where diced cartilage is wrapped in the periprosthetic capsule material formed from a previous breast augmentation procedure instead of fascia,a technique based on the Diced Cartilage in Fascia method.Utilizing autologous,biocompatible material minimizes foreign body reactions and enhances graft integration.This innovative approach demonstrates the potential for specific practices in cosmetic surgery by optimizing patient-specific resources and improving surgical outcomes.CONCLUSION The report compares traditional Turkish Delight applications with this new method,discussing biocompatibility,technique efficacy,and benefits in rhinoplasty.
文摘Cartilage,as a specialized connective tissue,underpins joint mobility and mech-anical load distribution while exhibiting inherently limited self-repair capabilities.This comprehensive review redefines the current landscape of cartilage imaging by exploring conventional and advanced modalities used to assess both the structural and biochemical attributes of cartilage.Whereas conventional radio-graphy and ultrasound offer rudimentary,indirect assessments,cutting-edge techniques-including magnetic resonance imaging(MRI)-based sequences such as T2 mapping,delayed gadolinium-enhanced MRI of cartilage,and sodium MRI-enable early detection of molecular alterations in the cartilage matrix.In ad-dition,hybrid approaches like positron emission tomography-MRI are emerging to provide integrative molecular and structural insights.This article critically appraises imaging strategies in the context of regenerative interventions,high-lighting technical innovations,persistent challenges,and future directions to facilitate improved diagnostic accuracy and therapeutic monitoring.
基金National Natural Science Foundation of China(82171003 and 82171002)Research and Develop Program of West China Hospital of Stomatology Sichuan University(NO.LCYJ-2022-YY-1)。
文摘Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,including bone and cartilage metabolism.Deletion of the core clock gene Bmal1 leads to pathological bone alterations,while the phenotypes are not consistent.Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism,but the exact regulatory mechanisms remain unclear.This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism,the upstream regulatory factors that control Bmal1,and the current Bmal1 knockout mouse models for research.We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.
基金funded by the Swiss National Science Foundation(#184912,in 2019)funding from the German Research Foundation(SFB 1483,in 2021).
文摘Purpose:This study aimed to assess the influence of older vs.younger age and previous anterior cruciate ligament(ACL)injury on resting serum cartilage oligomeric matrix protein(sCOMP(t_(pre)))concentration,on immediate load-induced sCOMP kinetics after a 30-min treadmill walking stress(ΔsCOMP(t_(post))),and on the dose-response relationship between ambulatory load magnitude andΔsCOMP(t_(post)).Methods:A total of 85 participants were recruited in 4 groups(20-30 years:24 healthy,23 ACL-injured;40-60 years:23 healthy,15 ACL-injured).Blood samples were collected immediately before and after a walking stress at 80%,100%,or 120%bodyweight(BW)on 3 test days and analyzed for sCOMP concentration.Linear models were used to estimate the effect of age,knee status(unilateral ACL injury,2-10 years prior),and sex on sCOMP(t_(pre)),ΔsCOMP(t_(post)),and the dose-re sponse between ambulatory load magnitude andΔsCOMP(t_(post)).Results:We found that sCOMP(t_(pre))was 21%higher in older than younger participants(p<0.001)but did not differ between ACL-injured and healthy participants(p=0.632).Also,ΔsCOMP(t_(post))was 19%lower in older than younger participants(p=0.030)and increased with body mass index(p<0.001),sCOMP(t_(pre))(p=0.008),and with 120%BW(p<0.001),independent of age,ACL injury,or sex.Conclusion:Age but not prior ACL injury influences resting sCOMP and load-induced sCOMP.The dose-response relationship between ambulatory load magnitude and load-induced sCOMP changes is not affected by age,ACL injury,or sex.A better understanding of systemic sCOMP and the role of its mechanoresponse for the understanding of osteoarthritis pathophysiology and monitoring intervention efficacy may require knowledge of individual cartilage composition and tissue-level loading parameters.
基金supported by the Natural Science Foundation of Guangdong Province(No.2022A1515012279)the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515110126)。
文摘Repairing and regenerating cartilage defects in osteoarthritis patients remains challenging.Traditional treatments primarily offer symptom relief without addressing the underlying progression of the disease.Stem cell therapies provide a promising solution,yet they face limitations such as short retention times,low survival rates in vivo,and insufficient extracellular matrix(ECM)production.Stem cell-based hydrogel therapy offers a controlled microenvironment that can mitigate these challenges and enhance cell therapy effectiveness.This review evaluates the advantages and limitations of various stem cell types and hydrogel materials,summarizing recent advances in their combination for cartilage repair.The potential of stem cell-hydrogel therapies is highlighted,along with the remaining challenges and future directions for improving their clinical application.
基金supported by the National Key Research and Development Program of China(2022YFA1106800)the National Natural Science Foundation of China(T2121004,82394441,92268203).
文摘Mitochondria are vital organelles whose impairment leads to numerous metabolic disorders.Mitochondrial transplantation serves as a promising clinical therapy.However,its widespread application is hindered by the limited availability of healthy mitochondria,with the dose required reaching up to 109 mitochondria per injection/patient.This necessitates sustainable and tractable approaches for producing high-quality human mitochondria.In this study,we demonstrated a highly efficient mitochondriaproducing strategy by manipulating mitobiogenesis and tuning organelle balance in human mesenchymal stem cells(MSCs).Utilizing an optimized culture medium(mito-condition)developed from our established formula,we achieved an 854-fold increase in mitochondria production compared to normal MSC culture within 15 days.These mitochondria were not only significantly expanded but also exhibited superior function both before and after isolation,with ATP production levels reaching 5.71 times that of normal mitochondria.Mechanistically,we revealed activation of the AMPK pathway and the establishment of a novel cellular state ideal for mitochondrial fabrication,characterized by enhanced proliferation and mitobiogenesis while suppressing other energy-consuming activities.Furthermore,the in vivo function of these mitochondria was validated in the mitotherapy in a mouse osteoarthritis model,resulting in significant cartilage regeneration over a 12-week period.Overall,this study presented a new strategy for the off-the-shelf fabrication of human mitochondria and provided insights into the molecular mechanisms governing organelle synthesis.
基金Open access funding provided by Manipal Academy of Higher Education,Manipal.
文摘Osteoarthritis is a common aging-related disorder that is confined mostly to the chondral layer of joints(e.g., the knee) but can spread to bony layers over time. In its early stages, osteoarthritis has minimal symptoms;however, these gradually worsen over time and include joint pain, stiffness, loss of mobility, and inflammation. The exposed subchondral bone of a Grade 4 osteoarthritic knee is highly prone to erosion if left untreated due to persistent rubbing between the bones, which can lead to painful bone spurs. However, treating osteoarthritis is especially challenging due to the poor mitotic potential and low metabolic activity of chondrocytes. Although currently available tissue-engineered products(e.g., BST-CarGel■, TruFit■, and Atelocollagen■) can achieve structural reconstruction and tissue regeneration, final clinical outcomes can still be improved. Major challenges faced during clinical studies of tissue-engineered constructs include chondrocyte hypertrophy and the development of mechanically inferior fibrous tissue, among others. These issues can be addressed by selecting suitable biomaterial combinations, mimicking the three-dimensional(3D) architecture of the tissue matrix, and better controlling inflammation. Furthermore, it is crucial to generate essential signaling molecules within the articular cartilage ecosystem. This approach must also account for the microarchitecture of the affected joint and support the chondrogenic differentiation of mesenchymal stem cells. The use of tissue-engineered constructs has the potential to overcome each of these challenges, since materials can be modified for drug/biomolecule delivery while simultaneously facilitating the regeneration of robust articular cartilage. Three-dimensional printing has been successfully used in tissue engineering to achieve bioprinting. By manipulating conventional 3D printing techniques and the types of bioink used, many different types of bioprinting have emerged. Overall, these bioprinting techniques can be used to address various challenges associated with osteoarthritis treatment.
基金NIH and NIAMS Grants R21 AR081642(W.Y.),R01 AR066746(W.Y.),R01 AR080062(V.L.)and R01 AR83245(V.L.)supported by the Rhode Island Hospital Orthopaedic Foundation(W.Y.).
文摘The SH2 domain-containing protein tyrosine phosphatase 2(SHP2,also known as PTP2C),encoded by PTPN11,is ubiquitously expressed and has context-specific effects.It promotes RAS/MAPK signaling downstream of receptor tyrosine kinases,cytokine receptors,and extracellular matrix proteins,and was shown in various lineages to modulate cell survival,proliferation,differentiation,and migration.Over the past decade,PTPN11 inactivation in chondrocytes was found to cause metachondromatosis,a rare disorder characterized by multiple enchondromas and osteochondroma-like lesions.Moreover,SHP2 inhibition was found to mitigate osteoarthritis pathogenesis in mice,and abundant but incomplete evidence suggests that SHP2 is crucial for cartilage development and adult homeostasis,during which its expression and activity are tightly regulated transcriptionally and posttranslationally,and by varying sets of functional partners.Fully uncovering SHP2 actions and regulation in chondrocytes is thus fundamental to understanding the mechanisms underlying both rare and common cartilage diseases and to designing effective disease treatments.We here review current knowledge,highlight recent discoveries and controversies,and propose new research directions to answer remaining questions.
基金supported by the National Key Research and Development Program of China(2019YFA0905200).
文摘The treatment of prolonged inflammation and cartilage damage due to osteoarthritis(OA)is a major clinical challenge.We developed a comprehensive cartilage repair therapy using a dual drug-loaded nanocomposite hydrogel that leveraged the spatiotemporal immunomodulatory effects of a naturally degradable protein-based nanocomposite hydrogel.The hydrogel acted as a scaffold that created a favorable microenvironment for cartilage regeneration.The hydrogel recruited macrophages and human mesenchymal stem cells(hMSCs),which supported the growth and adhesion of osteoblasts,and degraded to provide nutrition.Silk protein nanoparticles were chemically cross-linked with kartogenin,and humanlike collagen was physically cross-linked with dexamethasone through hydrogen bonding.In the early stages of cartilage repair,a large quantity of dexamethasone was released.The dexamethasone acted as an anti-inflammatory agent and a spatiotemporal modulator of the polarization of M1 macrophages into M2 macrophages.In the middle and late stages of cartilage repair,kartogenin underwent sustained release from the hydrogel,inducing the differentiation of hMSCs into chondrocytes and maintaining chondrocyte stability.Therefore,kartogenin and dexamethasone acted synergistically to induce cartilage repair.In conclusion,we developed an integrated therapeutic system by constructing a cartilage regeneration microenvironment and inducing synergistic drug-based cartilage regeneration.The therapeutic system demonstrated satisfactory efficacy for repairing cartilage damage in rabbits.
基金Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education,No.NRF-2022R1I1A1A01068652.
文摘GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.
基金Supported by Yantai Science and Technology Innovation Development Plan Project,No.2023YD048.
文摘Articular cartilage damage caused by trauma or degenerative diseases such as osteoarthritis remains a major therapeutic challenge due to the tissue’s limited regenerative capacity.Traditional surgical interventions-including microfracture,autologous chondrocyte implantation,and osteochondral grafting-often result in the formation of biomechanically inferior fibrocartilage and fail to restore longterm joint function.In contrast,stem cell-based strategies have emerged as a promising approach for regenerating hyaline-like cartilage by combining the biological potential of mesenchymal stem cells and induced pluripotent stem cells with advances in tissue engineering.This review synthesizes the current understanding of cartilage structure and repair limitations,evaluates the regenerative potential of various stem cell sources,and highlights engineering innovations such as bioactive scaffolds,controlled growth factor delivery,and threedimensional bioprinting.We also examine key preclinical studies and early-phase clinical trials demonstrating the safety and efficacy of stem cell-based therapies.Finally,we explore future directions,including gene editing,exosome-based therapeutics,and personalized regenerative strategies,that may address remaining translational barriers.Collectively,stem cell-centered approaches offer a transformative avenue toward durable,functional cartilage repair and hold strong potential for clinical application.
基金supported by the National Natural Science Foundation of China(No.31670523)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.23KJB180005)+1 种基金the Natural Science Foundation of Jiangsu Province(No.BK20230690)Jiangsu Ocean University Graduate Research and Practice Innovation Program Project(No.KYCX2023-105).
文摘Bisphenol A(BPA)is a recognized estrogenic endocrine disruptor that poses a threat to the reproductive health of fish.However,it remains unclear whether and how paternal BPA exposure can lead to developmental toxicity in offspring.To explore the potential paternal BPA exposure impacts on craniofacial cartilage growth in offspring,male rare minnows were subjected to BPA and subsequently mated with normal females to produce progeny.Our results demonstrated that paternal BPA exposure resulted in increased malformation and delayed craniofacial cartilage development in the F1 offspring.Furthermore,BPA exposure led to differential expression of 28 miRNAs in paternal sperm in F0 generation(13 upregulated and 15 downregulated),among which 7 miRNAs were involved in the regulation of bone development.BPA also downregulated the expression of bmp2a and Runx1 during F1 embryonic development.The inhibited bmp2a expression might derive from BPA's stimulation of one miRNA,aca-miR-16a-5P,due to bmp2a being one of its target genes.Notably,paternal BPA exposure did not affect craniofacial cartilage development or gonadal development in the F2 generation.Overall,our study sheds light on the molecular mechanisms underlying the impact of paternal BPA exposure on facial chondrogenesis in offspring and provides theoretical support for the ecological protection of fish populations.
基金supported by the Regional Joint Key Funding Program of the National Natural Science Foundation of China(Grant No.U21A20353)the National Natural Science Foundation of China(Grant Nos.12272250,11972242 and 82172503)+2 种基金China Postdoctoral Science Foundation(Grant No.2020M680913)Shanxi Province Returned Overseas Foundation(Grant No.2022-081)the Shanxi Province Basic Research Program(Grant No.202203021212254).
文摘Abnormal biomechanics plays a central role in the development of knee osteoarthritis(KOA).Low-intensity laser therapy(LILT)is considered an applicable method for the treatment of osteoarthritis.Current research on LILT for the treatment of KOA has focused on the regeneration of articular cartilage.Its biomechanical changes in periarticular tissues have been less well studied,and its role in improving abnormal joint biomechanics is unclear.This study aimed to investigate the role of LILT in improving the biomechanical properties of muscle and cartilage in KOA joints to alleviate cartilage degradation.In this study,a semiconductor laser with a wavelength of 808 nm was used to perform laser interventions in a KOA rat model 3 days per week for 6 weeks.The results of muscle stretch tests showed that LILT could significantly reduce the modulus of elasticity of KOA soleus muscle.Hematoxylin and eosin staining showed that LILT significantly increased the cross-sectional area of the soleus muscle fibers.This suggests that LILT alleviated KOA-induced soleus muscle atrophy and restored the mechanical properties of the muscle tissue.The results of compressive elastic modulus and electrical impedance characterization of cartilage showed that laser intervention significantly increased the elastic modulus and resistivity of cartilage.Results from safranin o-fast green staining and immunohistochemistry showed that LILT significantly increased the synthesis of type II collagen in the cartilage matrix.This may be one of the potential mechanisms by which LILT improves the mechanical properties of cartilage.In addition,immunohistochemistry also showed that LILT reduced the expression of matrix metallo-proteinase-13 in cartilage and effectively inhibited the degradation of the cartilage matrix in KOA.In conclusion,the present study demonstrated that LILT alleviated the abnormal biomechanics of KOA joint tissues by improving the mechanical properties of joint muscles and cartilage,thereby slowing down the degradation of KOA cartilage.
文摘BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.
基金financed by the Hercules Foundation(project AKUL/13/47)funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 874837+2 种基金supported by the Flemish Government(department of Economy,Science and Innovation)through the Regenerative Medicine Crossing Borders(http://www.regmedxb.com)initiativeImages were recorded on a Zeiss LSM 780-SP Mai Tai HP DS(Cell and Tissue Imaging Cluster(CIC),Supported by Hercules AKUL/11/37 and FWO G.0929.15 to Pieter Vanden Berghe,University of Leuvensupported by Interne Fondsen KU Leuven/Internal Funds KU Leuven grant numbers C24M/22/058.
文摘Clinical translation of tissue-engineered advanced therapeutic medicinal products is hindered by a lack of patient-dependent and independent in-process biological quality controls that are reflective of in vivo outcomes.Recent insights into the mechanism of native bone repair highlight a robust path dependence.Organoid-based bottom-up developmental engineering mimics this pathdependence to design personalized living implants scaffold-free,with in-build outcome predictability.Yet,adequate(noninvasive)quality metrics of engineered tissues are lacking.Moreover,insufficient insight into the role of donor variability and biological sex as influencing factors for the mechanism toward bone repair hinders the implementation of such protocols for personalized bone implants.Here,male and female bone-forming organoids were compared to non-bone-forming organoids regarding their extracellular matrix composition,transcriptome,and secreted proteome signatures to directly link in vivo outcomes to quality metrics.As a result,donor variability in bone-forming callus organoids pointed towards two distinct pathways to bone,through either a hypertrophic cartilage or a fibrocartilaginous template.The followed pathway was determined early,as a biological sexdependent activation of distinct progenitor populations.Independent of donor or biological sex,a cartilage-to-bone transition was driven by a common panel of secreted factors that played a role in extracellular matrix remodeling,mineralization,and attraction of vasculature.Hence,the secreted proteome is a source of noninvasive biomarkers that report on biological potency and could be the missing link toward data-driven decision-making in organoid-based bone tissue engineering.
基金supported by the Shandong Provincial Natural Science Foundation(for the preparation of bionic scaffolds for bone and cartilage repair and their osteogenic wear resistance study)(ZR2022ME086).
文摘The primary objective of Cartilage Tissue Engineering(CTE)involves repairing or rebuilding impaired cartilage in an effort to restore joint functionality and enhance patients'quality of life.In this field,researchers are constantly exploring new materials and technologies to address the challenges posed by cartilage damage.Biomimetic hydrogels present several distinct advantages in articular cartilage repair when compared to conventional treatment methods like minimally invasive surgery,joint replacement,and drug therapies.These hydrogels effectively mimic the mechanical characteristics of natural cartilage while also promoting cell adhesion,proliferation,and differentiation through the inclusion of bioactive factors.This results in the creation of high-performance biomaterials,positioning them as a particularly promising therapeutic option.Recently,researchers have drawn inspiration from the intricate structures found in soft tissues to develop various types of biomimetic hydrogels.These innovative hydrogels find applications across various fields,such as biomedicine,tissue engineering,and flexible electronics.In tissue engineering,these materials serve as optimal scaffolds for cartilage regeneration and aid in restoring tissue function.Nevertheless,creating and manufacturing biomimetic hydrogels with complex designs,strong mechanical properties,and multifunctionality poses significant challenges.This paper reviews existing studies on natural and synthetic matrices for biomimetic hydrogels,explores the similarities between these hydrogels and natural cartilage,examines their biological and physical characteristics,discusses their advantages and limitations,and suggests future research avenues.
基金Supported by the Scientific Research Project of the Traditional Chinese Medicine Administration of Hubei Provincial Health Commission,No.ZY2025 L268.
文摘BACKGROUND Osteoarthritis(OA)remains a challenging degenerative joint disease with limited therapeutic interventions.AIM To investigate the potential of synovial mesenchymal stem cell(SMSC)-derived exosomes(SMSCs-Exos)delivering GrpE-like 1(GRPEL1)in promoting cartilage repair through phosphatase and tensin homolog-induced putative kinase 1(PINK1)-mediated mitophagy activation.METHODS A comprehensive research approach was employed,including bioinformatics analysis of gene expression datasets(GSE169077 and GSE114007),in vitro ex-periments with CHON-001 chondrocytes,and in vivo rat knee OA models.Experi-mental techniques encompassed gene expression profiling,immunofluorescence staining,western blot analysis,co-immunoprecipitation,cell proliferation and migration assays,and histological examinations.Exosomes were genetically modified to overexpress or knockdown GRPEL1,and their effects on cellular function and mitochondrial dynamics were systematically evaluated.RESULTS Bioinformatics analysis revealed GRPEL1 as a critical mitophagy-related gene with significantly altered expression in OA.In vitro studies demonstrated that GRPEL1-loaded SMSCs-Exos effectively counteracted interleukin-1 beta-induced cellular damage by enhancing chondrocyte proliferation and migration,preserving extracellular matrix integrity.Mechanistic investigations confirmed direct interaction between GRPEL1 and PINK1,leading to enhanced mitophagy activation.In vivo rat models substantiated these findings,showing significantly reduced cartilage damage,restored proteoglycan content,and improved joint structure in groups receiving GRPEL1-overexpressing exosomes.Key molecular changes included decreased reactive oxygen species,improved mitochondrial membrane potential,and increased mitophagy markers.CONCLUSION This study provides compelling evidence that SMSCs-Exos delivering GRPEL1 can effectively activate PINK1-mediated mitophagy,offering a promising therapeutic strategy for cartilage repair in OA.The research unveils a novel molecular mechanism for targeting mitochondrial dysfunction and presents a potential disease-modifying approach beyond current symptomatic treatments.
