Heterotopic ossification (HO) may cause pain, and can lead to loss of hip motion after total hip arthroplasty (THA). There is evidence that pulsed lavage may lower the incidence of HO formation. We assessed the effect...Heterotopic ossification (HO) may cause pain, and can lead to loss of hip motion after total hip arthroplasty (THA). There is evidence that pulsed lavage may lower the incidence of HO formation. We assessed the effect of pulsed lavage on the incidence of HO in 87 male patients after THA. All patients received an uncemented THA through a posterolateral approach. 39 patients were treated with pulsed lavage (index group) and 48 males were treated without pulsed lavage (historical control group, matched on aetiology, gender, surgical approach and type of prosthesis). Both groups followed the same postoperative treatment regimen. HO severity was scored in both groups according to the Brooker classification by three blinded orthopaedic surgeons one year postoperatively. Good inter-observer agreement (Kappa 0.7) for scoring HO was found. The incidence of HO (51%) in the index group did not differ significantly (p = 0.53) from the control group (58%). However, the incidence of clinically relevant HO (Brooker grades 3 and 4) was significantly lower (p = 0.04) in the index group (3%) as compared to the control group (17%). These results suggest a beneficial effect of pulsed lavage on the incidence of severe heterotopic ossification after cementless THA in male patients.展开更多
Metal debris from metal-on-metal (MoM) total hip arthroplasties (THA) has been suspected to cause periprosthetic heterotopic ossifications (HO). We determined the influence of disseminated cobalt, chromium and molybde...Metal debris from metal-on-metal (MoM) total hip arthroplasties (THA) has been suspected to cause periprosthetic heterotopic ossifications (HO). We determined the influence of disseminated cobalt, chromium and molybdenum on the development of HO. Native blood samples from patients with 86 high-carbon and 16 low-carbon Co28Cr6Mo articulations were analysed by high-resolution inductively coupled plasma mass-spectrometry (HR ICP-MS). The results revealed that high-carbon metal-on-metal articulations showed lower metal blood levels (Co 1.03 to 1.60 μg/l, Cr 0.77 to 0.88 μg/l, Mo 0.45 to 0.56 μg/l) whereas low-carbon articulations achieved higher metal blood levels (Co 2.59 to 6.85 μg/l, Cr 1.25 to 3.55 μg/l, Mo 0.45 to 0.64 μg/l), but no correlation between metal ion blood level or carbon content and the development of HO could be found in these MoM articulations. Hence, metal debris from MoM articulation does not stimulate heterotopic bone formation despite other well-known local reactions.展开更多
Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and ...Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and the underlying mechanism remain elusive.Here,we show that the mechanical protein Polysyctin-1(PC1,Pkd1)regulates CTSK lineage tendon-derived mesenchymal stem cell(TDMSC)fate and ECM organization,thus affecting HO progression.First,we revealed that CTSK lineage TDMSCs are the major source of osteoblasts and fibroblasts in HO and are responsive to mechanical cues via single-cell RNA sequencing analysis and experiments with a lineage tracing mouse model.Moreover,we showed that PC1 mediates the mechanosignal transduction of CTSK lineage TDMSCs to regulate osteogenic and fibrogenic differentiation and alters the ECM architecture by facilitating TAZ nuclear translocation.Conditional gene depletion of Pkd1 or Taz in CTSK lineage cells and pharmaceutical intervention in the PC1-TAZ axis disrupt osteogenesis,fibrogenesis and ECM organization,and consequently attenuate HO progression.These findings suggest that mechanically sensitive CTSK-lineage TDMSCs contribute to heterotopic ossification through PC1-TAZ signaling axis mediated cell fate determination and ECM organization.展开更多
Survival of motor neuron(SMN)protein encoded by SMN1 gene,is the essential and ubiquitously expressed protein in all tissues.Prior studies demonstrated that SMN deficiency impaired bone development,but the underlying ...Survival of motor neuron(SMN)protein encoded by SMN1 gene,is the essential and ubiquitously expressed protein in all tissues.Prior studies demonstrated that SMN deficiency impaired bone development,but the underlying mechanism of abnormal endochondral ossification remains obscure.Here,we showed SMN is involved in hypertrophic chondrocytes differentiation through regulating RNA splicing and protein degradation via analyzing single cell RNA-sequencing data of hypertrophic chondrocytes.Of note,SMN loss induced dwarfism and delayed endochondral ossification in Smn1 depletion-severe spinal muscular atrophy(SMA)mouse model and Smn1 chondrocyte conditional knockdown mouse.Histological analysis revealed that SMN deficiency expanded the zone of hypertrophic chondrocytes in the growth plates,but delayed turnover from hypertrophic to ossification zone.Widespread changes in endochondral ossification related gene expression and alternative splicing profiles were identified via RNA sequencing of growth plate cartilages from SMA mice on postnatal day 4.Importantly,Mass spectrometry-based proteomics analysis elucidated Y-box-binding protein 1(YBX1)as a vital SMN-binding factor,was decreased in SMA mice.YBX1 knockdown reproduced the aberrant gene expression and splicing changes observed in SMA growth plate cartilages.Comparing the binding proteins of SMN and YBX1 revealed TNF receptor-associated factor 6(TRAF6),which promoted ubiquitination degradation of YBX1.By conditionally deleting Smn1 in chondrocytes of WT mice and overexpressing Smn1 in chondrocytes of SMA mice,we proved that SMN expression in chondrocytes is critical for hypertrophic chondrocyte-mediated endochondral ossification.Collectively,these results demonstrate that SMN deficiency contributes to rapid systemic bone dysplasia syndrome by promoting TRAF6-induced ubiquitination degradation of YBX1 in growth plate cartilages of SMA mice.展开更多
Piezo1,a key mechanosensor in bone homeostasis,plays a crucial role in fracture healing.However,the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood...Piezo1,a key mechanosensor in bone homeostasis,plays a crucial role in fracture healing.However,the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood.This study aimed to investigate the regulatory mechanisms of Piezo1 in chondrocytes during endochondral ossification.Using lineage tracing,we identified chondrocyte-to-osteoblast transdifferentiation during endochondral ossification,which was impaired by chondrocyte-specific Piezo1 knockout.Piezo1 deficiency disrupted mitochondrial bioenergetics,characterized by diminished membrane potential,reduced adenosine triphosphate(ATP)synthesis,suppressed oxygen consumption rates(basal and maximal respiration),and elevated mitochondrial superoxide generation,thereby impairing endochondral ossification during fracture healing.Single-cell RNA sequencing revealed upregulated Lars2 expression in hypertrophic chondrocytes following Piezo1 knockout.Inhibition of Lars2 in chondrocytes normalized mitochondrial dynamics-related markers(MFN1,MFN2,OPA1,DRP1)and restored mitochondrial functional homeostasis.This intervention concurrently reversed Piezo1 knockout-induced suppression of osteogenic markers(Col1,ALP,OCN,OPN,RUNX2),thereby enhancing fracture repair.Protein interaction analyses confirmed direct binding betweenβ-catenin and Lars2.Mechanistically,Piezo1 governs Lars2 expression viaβ-catenin signaling.Our findings demonstrate that Piezo1 activation via Yoda1 enhances mitochondrial bioenergetics and accelerates fracture repair through theβ-catenin/Lars2 axis,offering novel insights and therapeutic avenues for fracture treatment.展开更多
Heterotopic mesenteric ossification(HMO)is a rare medical condition,with<100 cases reported globally by 2024.This disorder is characterized by abnormal bone tissue formation within the mesentery,often following abd...Heterotopic mesenteric ossification(HMO)is a rare medical condition,with<100 cases reported globally by 2024.This disorder is characterized by abnormal bone tissue formation within the mesentery,often following abdominal trauma,ischemia,or infection.This editorial reviews the case presented by Zhang et al,involving a 34-year-old male who developed persistent left lower abdominal pain after sustaining blunt trauma to the abdomen.Diagnostic challenges arose due to the rarity and nonspecific presentation of HMO,which shares histopathological features with conditions such as myositis ossificans and necessitates differentiation from malignancies like sarcomas.Advanced imaging revealed calcifications suggestive of HMO,but definitive diagnosis was achieved only through surgical resection and histopathological analysis,which confirmed the presence of ectopic bone formation.Although benign,HMO can result in severe complications,such as bowel perforation or obstruction.Therefore,awareness of HMO is crucial for clinicians to ensure timely and appropriate treatment.展开更多
BACKGROUND Among all forms of heterotopic ossification,heterotopic mesenteric ossification(HMO)is rare,with fewer than 100 reported cases to date.Postoperative early small bowel obstruction caused by HMO is even rarer...BACKGROUND Among all forms of heterotopic ossification,heterotopic mesenteric ossification(HMO)is rare,with fewer than 100 reported cases to date.Postoperative early small bowel obstruction caused by HMO is even rarer,presenting extremely high surgical risks,the potential for multiple surgeries,and a poor prognosis.There have been no reported cases of conservative treatment for resolving such early postoperative obstruction.CASE SUMMARY A 57-year-old male presented with severe postoperative small bowel obstruction shortly after undergoing open radical resection for transverse colon cancer.Laparotomy revealed extensive adhesions in the proximal jejunum and mesen-tery,making it too difficult to relieve without injuring the small bowel.Addi-tionally,multiple fixed nodules were found in the mesentery during the opera-tion.Pathology confirmed the presence of heterotopic ossification.The patient was treated with methylprednisolone on postoperative day 1,which gradually relieved his symptoms.CONCLUSION Hormone therapy may have a potential role in treating small bowel obstruction caused by early HMO after operative intervention.展开更多
In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to elimin...In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.展开更多
Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GN...Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GNAQ,GNA11,or GNB2 gene[1],leading to vascular malformations in the cutaneous forehead,cerebral cortex,and eye[1,2].Notably,~70%of pediatric patients diagnosed with SWS exhibit brain calcification(BC)[4],though the prevalence of BC ranges from only 1%in young individuals to>20%in the senior population(>60 years old)[5].Similar to the elderly,BC in pediatric SWS patients is identified as vascular calcification[6,7],whereas BC in pediatric patients with tuberous sclerosis and tumors has been previously described as dystrophic calcification[6].展开更多
Ossification of the posterior longitudinal ligament(OPLL)is a degenerative disease characterized by progressive ectopic bone formation process,which can lead to severe neurological impairments and reduced quality of l...Ossification of the posterior longitudinal ligament(OPLL)is a degenerative disease characterized by progressive ectopic bone formation process,which can lead to severe neurological impairments and reduced quality of life.While the etiology of OPLL is generally considered multifactorial,there is no consensus regarding these contributing factors including genetic,endocrine,biomechanical,immune and lifestyle factors.Through accumulating evidence from multidisciplinary investigations,the pathophysiological connection between OPLL and endocrine-metabolic dysregulation is becoming increasingly clear.Nevertheless,comprehensive understanding of the relationship between the two is hindered by several problems,such as methodological limitations and inadequate mechanistic studies.This review takes a deep dive into the possible factors contributing to OPLL from all aspects of metabolism,including glucose metabolism,lipid metabolism,bone and mineral metabolism,leptin,vitamin,growth hormone/IGF-1 and sex hormones,highlighting their potential roles in the onset and progression of OPLL.Clarifying the etiology of OPLL and elucidating the underlying pathogenesis are crucial for advancing both early intervention strategies and therapeutic approaches in clinical management.Therefore,the endocrine and metabolic disorders in OPLL patients should become a focus of future research.展开更多
BACKGROUND Thoracic ossification of the posterior longitudinal ligament(T-OPLL)is caused by the ossified posterior longitudinal ligament occupying space in the spinal canal,which causes compression of the thoracic spi...BACKGROUND Thoracic ossification of the posterior longitudinal ligament(T-OPLL)is caused by the ossified posterior longitudinal ligament occupying space in the spinal canal,which causes compression of the thoracic spinal cord.Surgical treatment is difficult,risky and complicated;thus,clinical treatment is difficult at present.CASE SUMMARY A case of severe multi-segmental T-OPLL treated with thoracic anterior controllable antedisplacement fusion(TACAF)is reported,including the surgical procedures and analysis of the clinical data.The modified-Japanese Orthopaedic Association score in this patient was 4 before surgery,and it was raised to 9 after the operation.The symptoms of spinal canal compression were subsequently relieved.Three months after surgery,digital radiography showed good healing and recovery of limb sensory function.CONCLUSION This case report suggests that TACAF is feasible for the treatment of long-segment T-OPLL,and has the advantages of low risk and reduced trauma.However,this operation still needs to be verified by clinical research with a larger sample size.展开更多
Fibrodysplasia ossificans progressiva(FOP)is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive,extensive,and irreversible heterotopic ossification(HO)of soft t...Fibrodysplasia ossificans progressiva(FOP)is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive,extensive,and irreversible heterotopic ossification(HO)of soft tissues throughout the body,leading to severe disabilities.FOP is caused primarily by mutations in activin A receptor type 1(ACVR1),also known as activin-like kinase 2(ALK2),which encodes a receptor belonging to the bone morphogenetic protein(BMP)type I family.However,the continuous and complex process of HO in FOP is not yet fully understood,which has impeded the development of therapeutic drugs.Despite surgical removal of HO,which often results in recurrence and expansion of ossification,there is currently no definitive drug treatment available to completely prevent,halt,or reverse the progression of HO in FOP.Currently,researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates,including saracatinib,palovarotene,and rapamycin.This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs,with the goal of providing insights for further research and the development of new treatment methods.展开更多
脊柱韧带骨化性疾病是一类临床常见的多因素迟发性疾病,起病隐匿,常引起脊髓和神经根病变,以多种脊柱韧带骨化为特征,包括后纵韧带骨化（ossification of the posterior longitudinal ligament,OPLL）、黄韧带骨化（ossification of the...脊柱韧带骨化性疾病是一类临床常见的多因素迟发性疾病,起病隐匿,常引起脊髓和神经根病变,以多种脊柱韧带骨化为特征,包括后纵韧带骨化（ossification of the posterior longitudinal ligament,OPLL）、黄韧带骨化（ossification of the ligamentum flavum,OLF）和弥漫性特发性骨肥大症（diffuse idiopathic skeletal hyperostosis,DISH）[1]。展开更多
颈椎后纵韧带骨化症（ossification of the posterior longitudinal ligament,OPLL）是骨科常见的一种退行性疾病,起病隐匿,早期可无临床症状,待骨化的韧带组织增大到超过脊髓的耐受力时,可引起不同程度的神经功能障碍[1]。手术是治疗O...颈椎后纵韧带骨化症（ossification of the posterior longitudinal ligament,OPLL）是骨科常见的一种退行性疾病,起病隐匿,早期可无临床症状,待骨化的韧带组织增大到超过脊髓的耐受力时,可引起不同程度的神经功能障碍[1]。手术是治疗OPLL最直接有效的方法,短节段或孤立型OPLL可尝试行颈前路切除减压.展开更多
We report a unique case of lumbar disc herniation, in particular, with end-plate and surrounded by extensive ossification, mimicking a tumor with calcification. A 69-year-old female suffered from right buttock and leg...We report a unique case of lumbar disc herniation, in particular, with end-plate and surrounded by extensive ossification, mimicking a tumor with calcification. A 69-year-old female suffered from right buttock and leg pain. Computed tomography (CT) showed an intracanalar mass with calcification or ossification, which most likely originated from the vertebral body at the L1/2 level epidural space. On a T1-weighted gadolinium magnetic resonance image, the capsule of the mass was enhanced and not only the content of the mass but also that of the L2 vertebral body were partially and slightly enhanced. The final pathological diagnosis was disc herniation with end-plate fracture and secondary ossification. A combination of these pathological conditions as accompanied by both end-plate fractures and extensive secondary ossifications has not been previously reported. This rare pathological condition needs to be recognized as a differential diagnosis.展开更多
本研究对28例行椎管成形术的颈椎颈椎后纵韧带骨化症（ossification of the posterior longitudinal ligament,OPLL）患者进行系统护理及康复指导,并与对照组进行比较,进而观察其对患者神经功能恢复及AS的影响。报告如下。1资料与方法1....本研究对28例行椎管成形术的颈椎颈椎后纵韧带骨化症（ossification of the posterior longitudinal ligament,OPLL）患者进行系统护理及康复指导,并与对照组进行比较,进而观察其对患者神经功能恢复及AS的影响。报告如下。1资料与方法1.1临床资料选择2010年3月至2013年2月在我院治疗的56例颈椎OPLL患者,展开更多
Osteogenesis and angiogenesis are two closely correlated processes during bone growth, development, remodelling and repair. Vascular endothelial growth factor （VEGF） is an essential mediator during the process of an...Osteogenesis and angiogenesis are two closely correlated processes during bone growth, development, remodelling and repair. Vascular endothelial growth factor （VEGF） is an essential mediator during the process of angiogenesis. Based on an extensive literature search, which was carried out using the PubMed database and the keywords of osteogenesis, VEGF, endochondral ossification and intramembranous ossification, this manuscript reviews the role of VEGF in ossification, with emphasis on its effect in endochondral and intramembranous ossification. Osteogenesis and angiogenesis are closely correlated processes. VEGF acts as an essential mediator durin~ these processes. It not only functions in bone an^io^enesis but also in various aspects of bone develooment.展开更多
Ankylosing spondylitis(AS)is chronic inflammatory arthritis with a progressive fusion of axial joints.Anti-inflammatory treatments such as anti-TNF-αantibody therapy suppress inflammation but do not effectively halt ...Ankylosing spondylitis(AS)is chronic inflammatory arthritis with a progressive fusion of axial joints.Anti-inflammatory treatments such as anti-TNF-αantibody therapy suppress inflammation but do not effectively halt the progression of spine fusion in AS patients.Here we report that the autoimmune inflammation of AS generates a microenvironment that promotes chondrogenesis in spine ligaments as the process of spine fusion.Chondrocyte differentiation was observed in the ligaments of patients with earlystage AS,and cartilage formation was followed by calcification.Moreover,a large number of giant osteoclasts were found in the inflammatory environment of ligaments and on bony surfaces of calcified cartilage.Resorption activity by these giant osteoclasts generated marrow with high levels of active TGF-β,which induced new bone formation in the ligaments.Notably,no Osterix+osteoprogenitors were found in osteoclast resorption areas,indicating uncoupled bone resorption and formation.Even at the late and maturation stages,the uncoupled osteoclast resorption in bony interspinous ligament activates TGF-βto induce the progression of ossification in AS patients.Osteoclast resorption of calcified cartilage-initiated ossification in the progression of AS is a similar pathologic process of acquired heterotopic ossification(HO).Our finding of cartilage formation in the ligaments of AS patients revealed that the pathogenesis of spinal fusion is a process of HO and explained why anti-inflammatory treatments do not slow ankylosing once there is new bone formation in spinal soft tissues.Thus,inhibition of HO formation,such as osteoclast activity,cartilage formation,or TGF-βactivity could be a potential therapy for AS.展开更多
Intermuscular bones(IBs)are slender linear bones embedded in muscle,which ossify from tendons through a process of intramembranous ossification,and only exist in basal teleosts.IBs are essential for fish swimming,but ...Intermuscular bones(IBs)are slender linear bones embedded in muscle,which ossify from tendons through a process of intramembranous ossification,and only exist in basal teleosts.IBs are essential for fish swimming,but they present a choking risk during human consumption,especially in children,which can lead to commercial risks that have a negative impact on the aquaculture of these fish.In this review,we discuss the morphogenesis and functions of IBs,including their underlying molecular mechanisms,as well as the advantages and disadvantages of different methods for IB studies and techniques for breeding and generating IB-free fish lines.This review reveals that the many key genes involved in tendon development,osteoblast differentiation,and bone formation,e.g.,scxa,msxC,sost,twist,bmps,and osterix,also play roles in IB development.Thus,this paper provides useful information for the breeding of new fish strains without IBs via genome editing and artificial selection.展开更多
Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteo...Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage.Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)development.Mice with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate postnatally.Moreover,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth plates.While skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age.Likewise,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage degeneration.Importantly,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) mice.We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes.Finally,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes.Collectively,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.展开更多
文摘Heterotopic ossification (HO) may cause pain, and can lead to loss of hip motion after total hip arthroplasty (THA). There is evidence that pulsed lavage may lower the incidence of HO formation. We assessed the effect of pulsed lavage on the incidence of HO in 87 male patients after THA. All patients received an uncemented THA through a posterolateral approach. 39 patients were treated with pulsed lavage (index group) and 48 males were treated without pulsed lavage (historical control group, matched on aetiology, gender, surgical approach and type of prosthesis). Both groups followed the same postoperative treatment regimen. HO severity was scored in both groups according to the Brooker classification by three blinded orthopaedic surgeons one year postoperatively. Good inter-observer agreement (Kappa 0.7) for scoring HO was found. The incidence of HO (51%) in the index group did not differ significantly (p = 0.53) from the control group (58%). However, the incidence of clinically relevant HO (Brooker grades 3 and 4) was significantly lower (p = 0.04) in the index group (3%) as compared to the control group (17%). These results suggest a beneficial effect of pulsed lavage on the incidence of severe heterotopic ossification after cementless THA in male patients.
文摘Metal debris from metal-on-metal (MoM) total hip arthroplasties (THA) has been suspected to cause periprosthetic heterotopic ossifications (HO). We determined the influence of disseminated cobalt, chromium and molybdenum on the development of HO. Native blood samples from patients with 86 high-carbon and 16 low-carbon Co28Cr6Mo articulations were analysed by high-resolution inductively coupled plasma mass-spectrometry (HR ICP-MS). The results revealed that high-carbon metal-on-metal articulations showed lower metal blood levels (Co 1.03 to 1.60 μg/l, Cr 0.77 to 0.88 μg/l, Mo 0.45 to 0.56 μg/l) whereas low-carbon articulations achieved higher metal blood levels (Co 2.59 to 6.85 μg/l, Cr 1.25 to 3.55 μg/l, Mo 0.45 to 0.64 μg/l), but no correlation between metal ion blood level or carbon content and the development of HO could be found in these MoM articulations. Hence, metal debris from MoM articulation does not stimulate heterotopic bone formation despite other well-known local reactions.
基金National Natural Science Foundation of China(Grant Nos.82261160397,82272560)Central South University Research Programme of Advanced Interdisciplinary Studies(2023QYJC011)+4 种基金National Natural Science Foundation of China(Grant Nos.82472521,81922017)Hunan Provincial Science and Technology Department(2023JJ30896)Key Research and Development Program of Hunan Province(2022SK2023)Science and Technology Innovation Program of Hunan Province(2023RC1027)Major Basic Research Projects in Hunan Province(No.2024JC0004)。
文摘Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and the underlying mechanism remain elusive.Here,we show that the mechanical protein Polysyctin-1(PC1,Pkd1)regulates CTSK lineage tendon-derived mesenchymal stem cell(TDMSC)fate and ECM organization,thus affecting HO progression.First,we revealed that CTSK lineage TDMSCs are the major source of osteoblasts and fibroblasts in HO and are responsive to mechanical cues via single-cell RNA sequencing analysis and experiments with a lineage tracing mouse model.Moreover,we showed that PC1 mediates the mechanosignal transduction of CTSK lineage TDMSCs to regulate osteogenic and fibrogenic differentiation and alters the ECM architecture by facilitating TAZ nuclear translocation.Conditional gene depletion of Pkd1 or Taz in CTSK lineage cells and pharmaceutical intervention in the PC1-TAZ axis disrupt osteogenesis,fibrogenesis and ECM organization,and consequently attenuate HO progression.These findings suggest that mechanically sensitive CTSK-lineage TDMSCs contribute to heterotopic ossification through PC1-TAZ signaling axis mediated cell fate determination and ECM organization.
基金supported by the National Nature Science Foundation of China(81902179)the Postdoctoral Science Foundation of China(2020T130308)+3 种基金the Key Medical Discipline of Jiangsu Province(JSDW202223)the Natural Science Foundation of Jiangsu Province(BK20221241)the Science and Technology Project of Suzhou(SKJY2021094)the Gusu Talent Program(GSWS2022046)。
文摘Survival of motor neuron(SMN)protein encoded by SMN1 gene,is the essential and ubiquitously expressed protein in all tissues.Prior studies demonstrated that SMN deficiency impaired bone development,but the underlying mechanism of abnormal endochondral ossification remains obscure.Here,we showed SMN is involved in hypertrophic chondrocytes differentiation through regulating RNA splicing and protein degradation via analyzing single cell RNA-sequencing data of hypertrophic chondrocytes.Of note,SMN loss induced dwarfism and delayed endochondral ossification in Smn1 depletion-severe spinal muscular atrophy(SMA)mouse model and Smn1 chondrocyte conditional knockdown mouse.Histological analysis revealed that SMN deficiency expanded the zone of hypertrophic chondrocytes in the growth plates,but delayed turnover from hypertrophic to ossification zone.Widespread changes in endochondral ossification related gene expression and alternative splicing profiles were identified via RNA sequencing of growth plate cartilages from SMA mice on postnatal day 4.Importantly,Mass spectrometry-based proteomics analysis elucidated Y-box-binding protein 1(YBX1)as a vital SMN-binding factor,was decreased in SMA mice.YBX1 knockdown reproduced the aberrant gene expression and splicing changes observed in SMA growth plate cartilages.Comparing the binding proteins of SMN and YBX1 revealed TNF receptor-associated factor 6(TRAF6),which promoted ubiquitination degradation of YBX1.By conditionally deleting Smn1 in chondrocytes of WT mice and overexpressing Smn1 in chondrocytes of SMA mice,we proved that SMN expression in chondrocytes is critical for hypertrophic chondrocyte-mediated endochondral ossification.Collectively,these results demonstrate that SMN deficiency contributes to rapid systemic bone dysplasia syndrome by promoting TRAF6-induced ubiquitination degradation of YBX1 in growth plate cartilages of SMA mice.
基金supported by the Key Projects of the National Natural Science Foundation of China(Grant No.32130052)the National Natural Science Youth Foundation of China(Grant No.82102584)Natural Science Foundation of Hebei Province(CN)-for Yanzhao Young Scientists Project(Grant No.H2023206519).
文摘Piezo1,a key mechanosensor in bone homeostasis,plays a crucial role in fracture healing.However,the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood.This study aimed to investigate the regulatory mechanisms of Piezo1 in chondrocytes during endochondral ossification.Using lineage tracing,we identified chondrocyte-to-osteoblast transdifferentiation during endochondral ossification,which was impaired by chondrocyte-specific Piezo1 knockout.Piezo1 deficiency disrupted mitochondrial bioenergetics,characterized by diminished membrane potential,reduced adenosine triphosphate(ATP)synthesis,suppressed oxygen consumption rates(basal and maximal respiration),and elevated mitochondrial superoxide generation,thereby impairing endochondral ossification during fracture healing.Single-cell RNA sequencing revealed upregulated Lars2 expression in hypertrophic chondrocytes following Piezo1 knockout.Inhibition of Lars2 in chondrocytes normalized mitochondrial dynamics-related markers(MFN1,MFN2,OPA1,DRP1)and restored mitochondrial functional homeostasis.This intervention concurrently reversed Piezo1 knockout-induced suppression of osteogenic markers(Col1,ALP,OCN,OPN,RUNX2),thereby enhancing fracture repair.Protein interaction analyses confirmed direct binding betweenβ-catenin and Lars2.Mechanistically,Piezo1 governs Lars2 expression viaβ-catenin signaling.Our findings demonstrate that Piezo1 activation via Yoda1 enhances mitochondrial bioenergetics and accelerates fracture repair through theβ-catenin/Lars2 axis,offering novel insights and therapeutic avenues for fracture treatment.
基金Supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education,No.NRF-RS-2023-00237287 and No.NRF-2021S1A5A8062526Local Government-University Cooperation-Based Regional Innovation Projects,No.2021RIS-003.
文摘Heterotopic mesenteric ossification(HMO)is a rare medical condition,with<100 cases reported globally by 2024.This disorder is characterized by abnormal bone tissue formation within the mesentery,often following abdominal trauma,ischemia,or infection.This editorial reviews the case presented by Zhang et al,involving a 34-year-old male who developed persistent left lower abdominal pain after sustaining blunt trauma to the abdomen.Diagnostic challenges arose due to the rarity and nonspecific presentation of HMO,which shares histopathological features with conditions such as myositis ossificans and necessitates differentiation from malignancies like sarcomas.Advanced imaging revealed calcifications suggestive of HMO,but definitive diagnosis was achieved only through surgical resection and histopathological analysis,which confirmed the presence of ectopic bone formation.Although benign,HMO can result in severe complications,such as bowel perforation or obstruction.Therefore,awareness of HMO is crucial for clinicians to ensure timely and appropriate treatment.
基金Supported by Major Basic Research Project of Shanxi Provincial Natural Science Foundation,No.202203021221185 and No.202103021224379.
文摘BACKGROUND Among all forms of heterotopic ossification,heterotopic mesenteric ossification(HMO)is rare,with fewer than 100 reported cases to date.Postoperative early small bowel obstruction caused by HMO is even rarer,presenting extremely high surgical risks,the potential for multiple surgeries,and a poor prognosis.There have been no reported cases of conservative treatment for resolving such early postoperative obstruction.CASE SUMMARY A 57-year-old male presented with severe postoperative small bowel obstruction shortly after undergoing open radical resection for transverse colon cancer.Laparotomy revealed extensive adhesions in the proximal jejunum and mesen-tery,making it too difficult to relieve without injuring the small bowel.Addi-tionally,multiple fixed nodules were found in the mesentery during the opera-tion.Pathology confirmed the presence of heterotopic ossification.The patient was treated with methylprednisolone on postoperative day 1,which gradually relieved his symptoms.CONCLUSION Hormone therapy may have a potential role in treating small bowel obstruction caused by early HMO after operative intervention.
文摘In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.
基金supported by the Natural Science Foundation of Guangdong Province(2022A1515010297)the National Natural Science Foundation of China(32100765)+1 种基金the Xiamen Medical Health Science and Technology Project(3502Z20194098)the Shenzhen-Hong Kong-Macao Science and Technology Innovation Project(SGDX2020110309280100).
文摘Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GNAQ,GNA11,or GNB2 gene[1],leading to vascular malformations in the cutaneous forehead,cerebral cortex,and eye[1,2].Notably,~70%of pediatric patients diagnosed with SWS exhibit brain calcification(BC)[4],though the prevalence of BC ranges from only 1%in young individuals to>20%in the senior population(>60 years old)[5].Similar to the elderly,BC in pediatric SWS patients is identified as vascular calcification[6,7],whereas BC in pediatric patients with tuberous sclerosis and tumors has been previously described as dystrophic calcification[6].
文摘Ossification of the posterior longitudinal ligament(OPLL)is a degenerative disease characterized by progressive ectopic bone formation process,which can lead to severe neurological impairments and reduced quality of life.While the etiology of OPLL is generally considered multifactorial,there is no consensus regarding these contributing factors including genetic,endocrine,biomechanical,immune and lifestyle factors.Through accumulating evidence from multidisciplinary investigations,the pathophysiological connection between OPLL and endocrine-metabolic dysregulation is becoming increasingly clear.Nevertheless,comprehensive understanding of the relationship between the two is hindered by several problems,such as methodological limitations and inadequate mechanistic studies.This review takes a deep dive into the possible factors contributing to OPLL from all aspects of metabolism,including glucose metabolism,lipid metabolism,bone and mineral metabolism,leptin,vitamin,growth hormone/IGF-1 and sex hormones,highlighting their potential roles in the onset and progression of OPLL.Clarifying the etiology of OPLL and elucidating the underlying pathogenesis are crucial for advancing both early intervention strategies and therapeutic approaches in clinical management.Therefore,the endocrine and metabolic disorders in OPLL patients should become a focus of future research.
文摘BACKGROUND Thoracic ossification of the posterior longitudinal ligament(T-OPLL)is caused by the ossified posterior longitudinal ligament occupying space in the spinal canal,which causes compression of the thoracic spinal cord.Surgical treatment is difficult,risky and complicated;thus,clinical treatment is difficult at present.CASE SUMMARY A case of severe multi-segmental T-OPLL treated with thoracic anterior controllable antedisplacement fusion(TACAF)is reported,including the surgical procedures and analysis of the clinical data.The modified-Japanese Orthopaedic Association score in this patient was 4 before surgery,and it was raised to 9 after the operation.The symptoms of spinal canal compression were subsequently relieved.Three months after surgery,digital radiography showed good healing and recovery of limb sensory function.CONCLUSION This case report suggests that TACAF is feasible for the treatment of long-segment T-OPLL,and has the advantages of low risk and reduced trauma.However,this operation still needs to be verified by clinical research with a larger sample size.
基金supported by the National Natural Science Foundation of China(Nos.82370936,81920108012,81970903,and 82270959)the Jilin University Norman Bethune Program(No.2023B28)the Department of Finance of Jilin Province(No.jcsz2023481-37),China.
文摘Fibrodysplasia ossificans progressiva(FOP)is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive,extensive,and irreversible heterotopic ossification(HO)of soft tissues throughout the body,leading to severe disabilities.FOP is caused primarily by mutations in activin A receptor type 1(ACVR1),also known as activin-like kinase 2(ALK2),which encodes a receptor belonging to the bone morphogenetic protein(BMP)type I family.However,the continuous and complex process of HO in FOP is not yet fully understood,which has impeded the development of therapeutic drugs.Despite surgical removal of HO,which often results in recurrence and expansion of ossification,there is currently no definitive drug treatment available to completely prevent,halt,or reverse the progression of HO in FOP.Currently,researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates,including saracatinib,palovarotene,and rapamycin.This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs,with the goal of providing insights for further research and the development of new treatment methods.
文摘脊柱韧带骨化性疾病是一类临床常见的多因素迟发性疾病,起病隐匿,常引起脊髓和神经根病变,以多种脊柱韧带骨化为特征,包括后纵韧带骨化（ossification of the posterior longitudinal ligament,OPLL）、黄韧带骨化（ossification of the ligamentum flavum,OLF）和弥漫性特发性骨肥大症（diffuse idiopathic skeletal hyperostosis,DISH）[1]。
文摘颈椎后纵韧带骨化症（ossification of the posterior longitudinal ligament,OPLL）是骨科常见的一种退行性疾病,起病隐匿,早期可无临床症状,待骨化的韧带组织增大到超过脊髓的耐受力时,可引起不同程度的神经功能障碍[1]。手术是治疗OPLL最直接有效的方法,短节段或孤立型OPLL可尝试行颈前路切除减压.
文摘We report a unique case of lumbar disc herniation, in particular, with end-plate and surrounded by extensive ossification, mimicking a tumor with calcification. A 69-year-old female suffered from right buttock and leg pain. Computed tomography (CT) showed an intracanalar mass with calcification or ossification, which most likely originated from the vertebral body at the L1/2 level epidural space. On a T1-weighted gadolinium magnetic resonance image, the capsule of the mass was enhanced and not only the content of the mass but also that of the L2 vertebral body were partially and slightly enhanced. The final pathological diagnosis was disc herniation with end-plate fracture and secondary ossification. A combination of these pathological conditions as accompanied by both end-plate fractures and extensive secondary ossifications has not been previously reported. This rare pathological condition needs to be recognized as a differential diagnosis.
文摘本研究对28例行椎管成形术的颈椎颈椎后纵韧带骨化症（ossification of the posterior longitudinal ligament,OPLL）患者进行系统护理及康复指导,并与对照组进行比较,进而观察其对患者神经功能恢复及AS的影响。报告如下。1资料与方法1.1临床资料选择2010年3月至2013年2月在我院治疗的56例颈椎OPLL患者,
文摘Osteogenesis and angiogenesis are two closely correlated processes during bone growth, development, remodelling and repair. Vascular endothelial growth factor （VEGF） is an essential mediator during the process of angiogenesis. Based on an extensive literature search, which was carried out using the PubMed database and the keywords of osteogenesis, VEGF, endochondral ossification and intramembranous ossification, this manuscript reviews the role of VEGF in ossification, with emphasis on its effect in endochondral and intramembranous ossification. Osteogenesis and angiogenesis are closely correlated processes. VEGF acts as an essential mediator durin~ these processes. It not only functions in bone an^io^enesis but also in various aspects of bone develooment.
文摘Ankylosing spondylitis(AS)is chronic inflammatory arthritis with a progressive fusion of axial joints.Anti-inflammatory treatments such as anti-TNF-αantibody therapy suppress inflammation but do not effectively halt the progression of spine fusion in AS patients.Here we report that the autoimmune inflammation of AS generates a microenvironment that promotes chondrogenesis in spine ligaments as the process of spine fusion.Chondrocyte differentiation was observed in the ligaments of patients with earlystage AS,and cartilage formation was followed by calcification.Moreover,a large number of giant osteoclasts were found in the inflammatory environment of ligaments and on bony surfaces of calcified cartilage.Resorption activity by these giant osteoclasts generated marrow with high levels of active TGF-β,which induced new bone formation in the ligaments.Notably,no Osterix+osteoprogenitors were found in osteoclast resorption areas,indicating uncoupled bone resorption and formation.Even at the late and maturation stages,the uncoupled osteoclast resorption in bony interspinous ligament activates TGF-βto induce the progression of ossification in AS patients.Osteoclast resorption of calcified cartilage-initiated ossification in the progression of AS is a similar pathologic process of acquired heterotopic ossification(HO).Our finding of cartilage formation in the ligaments of AS patients revealed that the pathogenesis of spinal fusion is a process of HO and explained why anti-inflammatory treatments do not slow ankylosing once there is new bone formation in spinal soft tissues.Thus,inhibition of HO formation,such as osteoclast activity,cartilage formation,or TGF-βactivity could be a potential therapy for AS.
基金This work was supported by the National Natural Science Foundation of China(U1702233 and U1902202)Program of the Chinese Academy of Sciences(XDA24030505 and XDA23080502)Program of Yunnan Provincial Science and Technology Department(202003AD150017 and 2018FY001-007)。
文摘Intermuscular bones(IBs)are slender linear bones embedded in muscle,which ossify from tendons through a process of intramembranous ossification,and only exist in basal teleosts.IBs are essential for fish swimming,but they present a choking risk during human consumption,especially in children,which can lead to commercial risks that have a negative impact on the aquaculture of these fish.In this review,we discuss the morphogenesis and functions of IBs,including their underlying molecular mechanisms,as well as the advantages and disadvantages of different methods for IB studies and techniques for breeding and generating IB-free fish lines.This review reveals that the many key genes involved in tendon development,osteoblast differentiation,and bone formation,e.g.,scxa,msxC,sost,twist,bmps,and osterix,also play roles in IB development.Thus,this paper provides useful information for the breeding of new fish strains without IBs via genome editing and artificial selection.
基金supported by the German Research Foundation(SCHI 504/19-1(to TS)and IG 18/22-1(to AI))the Else Kröner-Fresenius foundation under grant no.2021_EKEA.23(to TR)financial support from the Open Access Publication Fund of UKE–Universitatsklinikum Hamburg-Eppendorf and DFG–German Research Foundation.
文摘Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage.Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)development.Mice with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate postnatally.Moreover,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth plates.While skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age.Likewise,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage degeneration.Importantly,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) mice.We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes.Finally,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes.Collectively,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.
