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
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
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
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
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
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
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
Neuromuscular electrical stimulation(NMES) and testosterone replacement therapy(TRT) are effective rehabilitation strategies to attenuate muscle atrophy and evoke hypertrophy in persons with spinal cord injury(SCI). H...Neuromuscular electrical stimulation(NMES) and testosterone replacement therapy(TRT) are effective rehabilitation strategies to attenuate muscle atrophy and evoke hypertrophy in persons with spinal cord injury(SCI). However both interventions might increase heterotopic ossification(HO) size in SCI patients. We present the results of two men with chronic traumatic motor complete SCI who also had pre-existing HO and participated in a study investigating the effects of TRT or TRT plus NMES resistance training(RT) on body composition. The 49-year-old male, Subject A, has unilateral HO in his right thigh. The 31-year-old male, Subject B, has bilateral HO in both thighs. Both participants wore transdermal testosterone patches(4-6 mg/d) daily for 16 wk. Subject A also underwent progressive NMES-RT twice weekly for 16 wk. Magnetic resonance imaging scans were acquired prior to and post intervention. Cross-sectional areas(CSA) of thewhole thigh and knee extensor skeletal muscles, femoral bone, and HO were measured. In Subject A(NMES-RT + TRT), the whole thigh skeletal muscle CSA increased by 10%, the knee extensor CSA increased by 17%, and the HO + femoral bone CSA did not change. In Subject B(TRT), the whole thigh skeletal muscle CSA increased by 13% in the right thigh and 6% in the left thigh. The knee extensor CSA increased by 7% in the right thigh and did not change in the left thigh. The femoral bone and HO CSAs in both thighs did not change. Both the TRT and NMES-RT + TRT protocols evoked muscle hypertrophy without stimulating the growth of preexisting HO.展开更多
Diffuse idiopathic skeletal hyperostosis(DISH) is a prevalent noninflammatory spondyloarthropathy characterized by ectopic mineral formation along the anterolateral aspect of the vertebral column, yet little is known ...Diffuse idiopathic skeletal hyperostosis(DISH) is a prevalent noninflammatory spondyloarthropathy characterized by ectopic mineral formation along the anterolateral aspect of the vertebral column, yet little is known about its underlying pathogenesis. Our objective was to evaluate the histopathological features and composition of ectopic mineral within spinal tissues affected by DISH in humans. Thoracic spine segments from six embalmed cadaveric donors(one female and five males;median age 82 years)meeting the radiographic diagnostic criteria for DISH were evaluated using radiological, histological, and physical analyses. Overall,the histological features of ectopic mineralization at individual motion segments were heterogeneous, including regions of heterotopic ossification and dystrophic calcification. Heterotopic ossifications were characterized by woven and lamellar bone,multifocal areas of metaplastic cartilage, and bony bridges along the anterior aspect of the intervertebral disc space. Dystrophic calcifications were characterized by an amorphous appearance, a high content of calcium and phosphorus, an X-ray diffraction pattern matching that of hydroxyapatite, and radiodensities exceeding that of cortical bone. Dystrophic calcifications were found within the anterior longitudinal ligament and annulus fibrosus in motion segments both meeting and not meeting the radiographic criteria for DISH. In summary, our findings indicate that in DISH, ectopic mineral forms along the anterior aspect of the spine by both heterotopic ossification and dystrophic calcification of fibrocartilaginous tissues. Although both types of ectopic mineralization are captured by current radiographic criteria for DISH, dystrophic calcification may reflect a distinct disease process or an early stage in the pathogenesis of DISH.展开更多
In our previous studies, we have found that the prepubertal increase in thyroid hormone levels induces osterix(Osx) signaling in hypertrophic chondrocytes to transdifferentiate them into osteoblasts. To test if Osx ex...In our previous studies, we have found that the prepubertal increase in thyroid hormone levels induces osterix(Osx) signaling in hypertrophic chondrocytes to transdifferentiate them into osteoblasts. To test if Osx expressed in chondrocytes directly contributes to transdifferentiation and secondary ossification, we generated Osx^flox/flox;Col2-Cre-ERT2 mice and knocked out Osx with a single injection of tamoxifen at postnatal day(P) 3 prior to evaluation of the epiphyseal bone phenotype by μCT, histology, and immunohistochemistry(IHC) at P21. Vehicle(oil)-treated Osx^flox/flox;Col2-Cre-ERT2 and tamoxifen-treated, Cre-negative Osx^flox/flox mice were used as controls.μCT analysis of tibial epiphyses revealed that trabecular bone mass was reduced by 23% in the Osx conditional knockout(c KO) compared with control mice. Trabecular number and thickness were reduced by 28% and 8%,respectively, while trabecular separation was increased by 24% in the c KO mice. Trichrome staining of longitudinal sections of tibial epiphyses showed that bone area and bone area adjusted for total area were decreased by 22% and 18%, respectively. IHC studies revealed the presence of abundant Osx-expressing prehypertrophic chondrocytes in the epiphyses of control mice at P10, but not in the cKO mice. Furthermore, expression levels of MMP13, COL10, ALP, and BSP were considerably reduced in the epiphyses of cKO mice. We also found that Osx overexpression in ATDC5 chondrocytes increased expression of Col10, Mmp13, Alp, and Bsp. Our data indicate that Osx expressed in chondrocytes plays a significant role in secondary ossification by regulating expression of genes involved in chondrocyte hypertrophy and osteoblast transdifferentiation.展开更多
Heterotopic ossification(HO)is a debilitating condition characterized by the pathologic formation of ectopic bone.HO occurs commonly following orthopedic surgeries,burns,and neurologic injuries.While surgical excision...Heterotopic ossification(HO)is a debilitating condition characterized by the pathologic formation of ectopic bone.HO occurs commonly following orthopedic surgeries,burns,and neurologic injuries.While surgical excision may provide palliation,the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone.Based on these clinical observations,we set out to examine the role of vascular signaling in HO.Vascular endothelial growth factor A(VEGFA)has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis.Our findings,using a validated mouse model of HO,demonstrate that HO lesions are highly vascular,and that VEGFA is critical to ectopic bone formation,despite lacking a contribution of endothelial cells within the developing anlagen.展开更多
AIM To present the incidence of heterotopic ossification after the use of recombinant human bone morphogenetic protein-7(rhB MP-7) for the treatment of nonunions.METHODS Bone morphogenetic proteins(BMPs) promote bone ...AIM To present the incidence of heterotopic ossification after the use of recombinant human bone morphogenetic protein-7(rhB MP-7) for the treatment of nonunions.METHODS Bone morphogenetic proteins(BMPs) promote bone formation by auto-induction. Recombinant human BMP-7 in combination with bone grafts was used in 84 patients for the treatment of long bone nonunions. All patients were evaluated radiographicaly for the development of heterotopic ossification during the standard assessment for the nonunion healing. In all patients(80.9%) with radiographic signs of heterotopic ossification, a CT scan was performed. Nonunion site palpation and ROM evaluation of the adjacent jointswere also carried out. Factors related to the patient(age, gender), the nonunion(location, size, chronicity, number of previous procedures, infection, surrounding tissues condition) and the surgical procedure(graft and fixation type, amount of rhB MP-7) were correlated with the development of heterotopic ossification and statistical analysis with Pearsons χ~2 test was performed.RESULTS Eighty point nine percent of the nonunions treated with rh BMP-7, healed with no need for further procedures. Heterotopic bone formation occurred in 15 of 84 patients(17.8%) and it was apparent in the routine radiologi-cal evaluation of the nonunion site, in a mean time of 5.5 mo after the rh BMP-7 application(range 3-12). The heterotopic ossification was located at the femur in 8 cases, at the tibia in 6, and at the humerus in οne patient. In 4 patients a palpable mass was present and only in one patient, with a para-articular knee nonunion treated with rhB MP-7, the size of heterotopic ossification affected the knee range of motion. All the patients with heterotopic ossification were male. Statistical analysis proved that patient's gender was the only important factor for the development of heterotopic ossification(P = 0.007). CONCLUSION Heterotopic ossification after the use of rh BMP-7 in nonunions was common but it did not compromise the final clinical outcome in most cases, and affected only male patients.展开更多
How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated i...How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated intramembranous ossification during cranial bone development in mouse models of skeletal genetic diseases that exhibit craniofacial bone defects. The GNAS gene encodes Gαs that transduces GPCR signaling. GNAS activation or loss-of-function mutations in humans cause fibrous dysplasia(FD) or progressive osseous heteroplasia(POH) that shows craniofacial hyperostosis or craniosynostosis, respectively. We find here that, while Hh ligand-dependent Hh signaling is essential for endochondral ossification, it is dispensable for intramembranous ossification, where Gαsregulates Hh signaling in a ligand-independent manner. We further show that Gαscontrols intramembranous ossification by regulating both Hh and Wnt/β-catenin signaling. In addition, Gαsactivation in the developing cranial bone leads to reduced ossification but increased cartilage presence due to reduced cartilage dissolution, not cell fate switch. Small molecule inhibitors of Hh and Wnt signaling can effectively ameliorate cranial bone phenotypes in mice caused by loss or gain of Gnas function mutations, respectively. Our work shows that studies of genetic diseases provide invaluable insights in both pathological bone defects and normal bone development, understanding both leads to better diagnosis and therapeutic treatment of bone diseases.展开更多
Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury.Inflammasome-related proteins encapsulated in brain-deri...Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury.Inflammasome-related proteins encapsulated in brain-derived extracellular vesicles can cross the blood‒brain barrier to reach distal tissues.These proteins initiate inflammatory dysfunction,such as neurogenic heterotopic ossification.This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies.Accordingly,a rat model of neurogenic heterotopic ossification induced by combined traumatic brain injury and achillotenotomy was developed to address these two issues.Histological examination of the injured tendon revealed the coexistence of ectopic calcification and fibroblast pyroptosis.The relationships among brain-derived extracellular vesicles,fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo.Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo.The present work highlights the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offers a potential strategy for preventing neurogenic heterotopic ossification after traumatic brain injury.展开更多
BACKGROUND Unsuspected gallbladder carcinoma(UGC)refers to cholecystectomy due to benign gallbladder disease,which is pathologically confirmed as gallbladder cancer during or after surgery.Port-site metastasis(PSM)of ...BACKGROUND Unsuspected gallbladder carcinoma(UGC)refers to cholecystectomy due to benign gallbladder disease,which is pathologically confirmed as gallbladder cancer during or after surgery.Port-site metastasis(PSM)of UGC following laparoscopic cholecystectomy is rare,especially after several years.CASE SUMMARY A 55-year-old man presenting with acute cholecystitis and gallstones was treated by laparoscopic cholecystectomy in July 2008.Histological analysis revealed unexpected papillary adenocarcinoma of the gallbladder with gallstones,which indicated that the tumor had spread to the muscular space(pT1b).Radical resection of gallbladder carcinoma was performed 10 d later.In January 2018,the patient was admitted to our hospital for a mass in the upper abdominal wall after surgery for gallbladder cancer 10 years ago.Laparoscopic exploration and complete resection of the abdominal wall tumor were successfully performed.Pathological diagnosis showed metastatic or invasive,moderately differentiated adenocarcinoma in fibrous tissue with massive ossification.Immunohistochemistry and medical history were consistent with invasion or metastasis of gallbladder carcinoma.His general condition was well at follow-up of 31 mo.No recurrence was found by ultrasound and epigastric enhanced computed tomography.CONCLUSION PSM of gallbladder cancer is often accompanied by peritoneal metastasis,which indicates poor prognosis.Once PSM occurs after surgery,laparoscopic exploration is recommended to rule out abdominal metastasis to avoid unnecessary surgery.展开更多
Mandibular defects caused by injuries,tumors,and infections are common and can severely affect mandibular function and the patient's appearance.However,mandible reconstruction with a mandibular bionic structure re...Mandibular defects caused by injuries,tumors,and infections are common and can severely affect mandibular function and the patient's appearance.However,mandible reconstruction with a mandibular bionic structure remains challenging.Inspired by the process of intramembranous ossification in mandibular development,a hierarchical vascularized engineered bone consisting of angiogenesis and osteogenesis modules has been produced.Moreover,the hierarchical vascular network and bone structure generated by these hierarchical vascularized engineered bone modules match the particular anatomical structure of the mandible.The ultra-tough polyion complex has been used as the basic scaffold for hierarchical vascularized engineered bone for ensuring better reconstruction of mandible function.According to the results of in vivo experiments,the bone regenerated using hierarchical vascularized engineered bone is similar to the natural mandibular bone in terms of morphology and genomics.The sonic hedgehog signaling pathway is specifically activated in hierarchical vascularized engineered bone,indicating that the new bone in hierarchical vascularized engineered bone underwent a process of intramembranous ossification identical to that of mandible development.Thus,hierarchical vascularized engineered bone has a high potential for clinical application in mandibular defect reconstruction.Moreover,the concept based on developmental processes and bionic structures provides an effective strategy for tissue regeneration.展开更多
Acute cauda equina syndrome is known as a symptom of lumbar disc herniation, but to date, there have been no reports of cases caused by lumbar vertebral ligament ossification. We encountered a 61-year-old female patie...Acute cauda equina syndrome is known as a symptom of lumbar disc herniation, but to date, there have been no reports of cases caused by lumbar vertebral ligament ossification. We encountered a 61-year-old female patient with acute cauda equina syndrome associated with lumbar vertebral OPLL and OLF. The symptoms were improved by emergency laminectomy. One year after the surgery, the disturbances of gait and urination have been resolved.展开更多
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 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 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].
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.
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.
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.
文摘Neuromuscular electrical stimulation(NMES) and testosterone replacement therapy(TRT) are effective rehabilitation strategies to attenuate muscle atrophy and evoke hypertrophy in persons with spinal cord injury(SCI). However both interventions might increase heterotopic ossification(HO) size in SCI patients. We present the results of two men with chronic traumatic motor complete SCI who also had pre-existing HO and participated in a study investigating the effects of TRT or TRT plus NMES resistance training(RT) on body composition. The 49-year-old male, Subject A, has unilateral HO in his right thigh. The 31-year-old male, Subject B, has bilateral HO in both thighs. Both participants wore transdermal testosterone patches(4-6 mg/d) daily for 16 wk. Subject A also underwent progressive NMES-RT twice weekly for 16 wk. Magnetic resonance imaging scans were acquired prior to and post intervention. Cross-sectional areas(CSA) of thewhole thigh and knee extensor skeletal muscles, femoral bone, and HO were measured. In Subject A(NMES-RT + TRT), the whole thigh skeletal muscle CSA increased by 10%, the knee extensor CSA increased by 17%, and the HO + femoral bone CSA did not change. In Subject B(TRT), the whole thigh skeletal muscle CSA increased by 13% in the right thigh and 6% in the left thigh. The knee extensor CSA increased by 7% in the right thigh and did not change in the left thigh. The femoral bone and HO CSAs in both thighs did not change. Both the TRT and NMES-RT + TRT protocols evoked muscle hypertrophy without stimulating the growth of preexisting HO.
基金supported by the Canadian Institutes of Health Research (grant number 115068)。
文摘Diffuse idiopathic skeletal hyperostosis(DISH) is a prevalent noninflammatory spondyloarthropathy characterized by ectopic mineral formation along the anterolateral aspect of the vertebral column, yet little is known about its underlying pathogenesis. Our objective was to evaluate the histopathological features and composition of ectopic mineral within spinal tissues affected by DISH in humans. Thoracic spine segments from six embalmed cadaveric donors(one female and five males;median age 82 years)meeting the radiographic diagnostic criteria for DISH were evaluated using radiological, histological, and physical analyses. Overall,the histological features of ectopic mineralization at individual motion segments were heterogeneous, including regions of heterotopic ossification and dystrophic calcification. Heterotopic ossifications were characterized by woven and lamellar bone,multifocal areas of metaplastic cartilage, and bony bridges along the anterior aspect of the intervertebral disc space. Dystrophic calcifications were characterized by an amorphous appearance, a high content of calcium and phosphorus, an X-ray diffraction pattern matching that of hydroxyapatite, and radiodensities exceeding that of cortical bone. Dystrophic calcifications were found within the anterior longitudinal ligament and annulus fibrosus in motion segments both meeting and not meeting the radiographic criteria for DISH. In summary, our findings indicate that in DISH, ectopic mineral forms along the anterior aspect of the spine by both heterotopic ossification and dystrophic calcification of fibrocartilaginous tissues. Although both types of ectopic mineralization are captured by current radiographic criteria for DISH, dystrophic calcification may reflect a distinct disease process or an early stage in the pathogenesis of DISH.
基金supported by the National Institutes of Health grant AR 048139 to S.M.
文摘In our previous studies, we have found that the prepubertal increase in thyroid hormone levels induces osterix(Osx) signaling in hypertrophic chondrocytes to transdifferentiate them into osteoblasts. To test if Osx expressed in chondrocytes directly contributes to transdifferentiation and secondary ossification, we generated Osx^flox/flox;Col2-Cre-ERT2 mice and knocked out Osx with a single injection of tamoxifen at postnatal day(P) 3 prior to evaluation of the epiphyseal bone phenotype by μCT, histology, and immunohistochemistry(IHC) at P21. Vehicle(oil)-treated Osx^flox/flox;Col2-Cre-ERT2 and tamoxifen-treated, Cre-negative Osx^flox/flox mice were used as controls.μCT analysis of tibial epiphyses revealed that trabecular bone mass was reduced by 23% in the Osx conditional knockout(c KO) compared with control mice. Trabecular number and thickness were reduced by 28% and 8%,respectively, while trabecular separation was increased by 24% in the c KO mice. Trichrome staining of longitudinal sections of tibial epiphyses showed that bone area and bone area adjusted for total area were decreased by 22% and 18%, respectively. IHC studies revealed the presence of abundant Osx-expressing prehypertrophic chondrocytes in the epiphyses of control mice at P10, but not in the cKO mice. Furthermore, expression levels of MMP13, COL10, ALP, and BSP were considerably reduced in the epiphyses of cKO mice. We also found that Osx overexpression in ATDC5 chondrocytes increased expression of Col10, Mmp13, Alp, and Bsp. Our data indicate that Osx expressed in chondrocytes plays a significant role in secondary ossification by regulating expression of genes involved in chondrocyte hypertrophy and osteoblast transdifferentiation.
基金B.L.:Supported by funding from NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH1R01AR071379American College of Surgeons Clowes Award.D.M.S.:Supported by Plastic Surgery Foundation Resident Research Award+6 种基金M.S.:Supported by Plastic Surgery Foundation National Endowment AwardC.H.:Supported by Howard Hughes Medical Institute Medical Research FellowshipJ.L.:Supported by Vascular Surgery T32 5-T32-HL-076123–14A.W.J.:Supported by the NIH/NIAMS(R01 AR070773,K08 AR068316,S10OD016374)the Orthopedic Research and Education Foundation with funding provided by the Maryland Stem Cell Research Foundation,and the Musculoskeletal Transplant FoundationP.B.Y.:Supported by funding from NIH/NIAMS R01 AR057374 and NHLBI R01 HL131910Y.M.:Supported by funding from NIH/NIDCR R01 DE020843 and DE027662
文摘Heterotopic ossification(HO)is a debilitating condition characterized by the pathologic formation of ectopic bone.HO occurs commonly following orthopedic surgeries,burns,and neurologic injuries.While surgical excision may provide palliation,the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone.Based on these clinical observations,we set out to examine the role of vascular signaling in HO.Vascular endothelial growth factor A(VEGFA)has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis.Our findings,using a validated mouse model of HO,demonstrate that HO lesions are highly vascular,and that VEGFA is critical to ectopic bone formation,despite lacking a contribution of endothelial cells within the developing anlagen.
基金The European Union(European Social Fund-ESF)Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework(NSRF)-Research Funding Program:Heracleitus Ⅱ
文摘AIM To present the incidence of heterotopic ossification after the use of recombinant human bone morphogenetic protein-7(rhB MP-7) for the treatment of nonunions.METHODS Bone morphogenetic proteins(BMPs) promote bone formation by auto-induction. Recombinant human BMP-7 in combination with bone grafts was used in 84 patients for the treatment of long bone nonunions. All patients were evaluated radiographicaly for the development of heterotopic ossification during the standard assessment for the nonunion healing. In all patients(80.9%) with radiographic signs of heterotopic ossification, a CT scan was performed. Nonunion site palpation and ROM evaluation of the adjacent jointswere also carried out. Factors related to the patient(age, gender), the nonunion(location, size, chronicity, number of previous procedures, infection, surrounding tissues condition) and the surgical procedure(graft and fixation type, amount of rhB MP-7) were correlated with the development of heterotopic ossification and statistical analysis with Pearsons χ~2 test was performed.RESULTS Eighty point nine percent of the nonunions treated with rh BMP-7, healed with no need for further procedures. Heterotopic bone formation occurred in 15 of 84 patients(17.8%) and it was apparent in the routine radiologi-cal evaluation of the nonunion site, in a mean time of 5.5 mo after the rh BMP-7 application(range 3-12). The heterotopic ossification was located at the femur in 8 cases, at the tibia in 6, and at the humerus in οne patient. In 4 patients a palpable mass was present and only in one patient, with a para-articular knee nonunion treated with rhB MP-7, the size of heterotopic ossification affected the knee range of motion. All the patients with heterotopic ossification were male. Statistical analysis proved that patient's gender was the only important factor for the development of heterotopic ossification(P = 0.007). CONCLUSION Heterotopic ossification after the use of rh BMP-7 in nonunions was common but it did not compromise the final clinical outcome in most cases, and affected only male patients.
基金supported by the NIH grants R01DE025866 from NIDCRR01AR070877 from NIAMSsupported by the 111 Project, MOE (B14038), China
文摘How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated intramembranous ossification during cranial bone development in mouse models of skeletal genetic diseases that exhibit craniofacial bone defects. The GNAS gene encodes Gαs that transduces GPCR signaling. GNAS activation or loss-of-function mutations in humans cause fibrous dysplasia(FD) or progressive osseous heteroplasia(POH) that shows craniofacial hyperostosis or craniosynostosis, respectively. We find here that, while Hh ligand-dependent Hh signaling is essential for endochondral ossification, it is dispensable for intramembranous ossification, where Gαsregulates Hh signaling in a ligand-independent manner. We further show that Gαscontrols intramembranous ossification by regulating both Hh and Wnt/β-catenin signaling. In addition, Gαsactivation in the developing cranial bone leads to reduced ossification but increased cartilage presence due to reduced cartilage dissolution, not cell fate switch. Small molecule inhibitors of Hh and Wnt signaling can effectively ameliorate cranial bone phenotypes in mice caused by loss or gain of Gnas function mutations, respectively. Our work shows that studies of genetic diseases provide invaluable insights in both pathological bone defects and normal bone development, understanding both leads to better diagnosis and therapeutic treatment of bone diseases.
基金This work was supported by the National Nature Science Foundation of China grant 82170978(to K.J.)the Distinguished Young Scientists Funds of Shannxi Province 2021JC-34(to K.J.).
文摘Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury.Inflammasome-related proteins encapsulated in brain-derived extracellular vesicles can cross the blood‒brain barrier to reach distal tissues.These proteins initiate inflammatory dysfunction,such as neurogenic heterotopic ossification.This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies.Accordingly,a rat model of neurogenic heterotopic ossification induced by combined traumatic brain injury and achillotenotomy was developed to address these two issues.Histological examination of the injured tendon revealed the coexistence of ectopic calcification and fibroblast pyroptosis.The relationships among brain-derived extracellular vesicles,fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo.Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo.The present work highlights the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offers a potential strategy for preventing neurogenic heterotopic ossification after traumatic brain injury.
文摘BACKGROUND Unsuspected gallbladder carcinoma(UGC)refers to cholecystectomy due to benign gallbladder disease,which is pathologically confirmed as gallbladder cancer during or after surgery.Port-site metastasis(PSM)of UGC following laparoscopic cholecystectomy is rare,especially after several years.CASE SUMMARY A 55-year-old man presenting with acute cholecystitis and gallstones was treated by laparoscopic cholecystectomy in July 2008.Histological analysis revealed unexpected papillary adenocarcinoma of the gallbladder with gallstones,which indicated that the tumor had spread to the muscular space(pT1b).Radical resection of gallbladder carcinoma was performed 10 d later.In January 2018,the patient was admitted to our hospital for a mass in the upper abdominal wall after surgery for gallbladder cancer 10 years ago.Laparoscopic exploration and complete resection of the abdominal wall tumor were successfully performed.Pathological diagnosis showed metastatic or invasive,moderately differentiated adenocarcinoma in fibrous tissue with massive ossification.Immunohistochemistry and medical history were consistent with invasion or metastasis of gallbladder carcinoma.His general condition was well at follow-up of 31 mo.No recurrence was found by ultrasound and epigastric enhanced computed tomography.CONCLUSION PSM of gallbladder cancer is often accompanied by peritoneal metastasis,which indicates poor prognosis.Once PSM occurs after surgery,laparoscopic exploration is recommended to rule out abdominal metastasis to avoid unnecessary surgery.
基金National Key Research and Development Program of China(2018YFA0703000)National Natural Science Foundation of China(8212200044,52075482,82071085,81873720)+2 种基金Zhejiang Provincial Natural Science Foundation of China(LR21H140001)Key Research and Development Program of Zhejiang,China(2017C01054,2018C03062)Scientific Research Fund of Zhejiang Provincial Education Department(Y202045564)。
文摘Mandibular defects caused by injuries,tumors,and infections are common and can severely affect mandibular function and the patient's appearance.However,mandible reconstruction with a mandibular bionic structure remains challenging.Inspired by the process of intramembranous ossification in mandibular development,a hierarchical vascularized engineered bone consisting of angiogenesis and osteogenesis modules has been produced.Moreover,the hierarchical vascular network and bone structure generated by these hierarchical vascularized engineered bone modules match the particular anatomical structure of the mandible.The ultra-tough polyion complex has been used as the basic scaffold for hierarchical vascularized engineered bone for ensuring better reconstruction of mandible function.According to the results of in vivo experiments,the bone regenerated using hierarchical vascularized engineered bone is similar to the natural mandibular bone in terms of morphology and genomics.The sonic hedgehog signaling pathway is specifically activated in hierarchical vascularized engineered bone,indicating that the new bone in hierarchical vascularized engineered bone underwent a process of intramembranous ossification identical to that of mandible development.Thus,hierarchical vascularized engineered bone has a high potential for clinical application in mandibular defect reconstruction.Moreover,the concept based on developmental processes and bionic structures provides an effective strategy for tissue regeneration.
文摘Acute cauda equina syndrome is known as a symptom of lumbar disc herniation, but to date, there have been no reports of cases caused by lumbar vertebral ligament ossification. We encountered a 61-year-old female patient with acute cauda equina syndrome associated with lumbar vertebral OPLL and OLF. The symptoms were improved by emergency laminectomy. One year after the surgery, the disturbances of gait and urination have been resolved.
