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 Heterotopic ossification(HO)refers to the formation of new bone in non-skeletal tissues such as muscles,tendons or other soft tissues.Severe muscle and soft tissue injury often lead to the formation of HO.H...BACKGROUND Heterotopic ossification(HO)refers to the formation of new bone in non-skeletal tissues such as muscles,tendons or other soft tissues.Severe muscle and soft tissue injury often lead to the formation of HO.However,anterior HO of the ankle is rarely reported.CASE SUMMARY We report a patient with massive HO in front of the ankle joint for 23 years.In 1998,the patient was injured by a falling object on the right lower extremity,which gradually formed a massive heterotopic bone change in the right calf and dorsum of the foot.The patient did not develop gradual ankle function limitations until nearly 36 mo ago,and underwent resection of HO.Even after 23 years and resection of HO,the ankle joint was still able to move.CONCLUSION It is recommended that the orthopedist should be aware of HO and distinguish it from bone tumor.展开更多
BACKGROUND Heterotopic ossification(HO)represents all types of extraskeletal ossification in the body.It occurs in various areas,including the skin,subcutaneous tissue,muscle,and joints.Surgical excision is recommende...BACKGROUND Heterotopic ossification(HO)represents all types of extraskeletal ossification in the body.It occurs in various areas,including the skin,subcutaneous tissue,muscle,and joints.Surgical excision is recommended for symptomatic HO.Postoperative radiotherapy,oral nonsteroidal anti-inflammatory drugs,and topical sealants,such as bone wax,have been recommended as preventive measures.As HO is rare in occurrence,these recommendations are based on personal experiences,and there is a lack of information on individualized treatments depending on its location.CASE SUMMARY A 62-year-old male was admitted for symptomatic HO along a laparotomy scar.Surgical excision was performed for an 11 cm-sized ossification originating from the xiphoid process,and bone wax was applied to the excisional margin.However,the surgical wound failed to heal.After several weeks of saline-soaked gauze dressing,delayed wound closure was performed.The patient was finally discharged eight weeks after the excision.Because HO can occur in various areas of the body,a treatment strategy that may be effective for some may not be for others.Bone wax has been used as a topical sealant over excisional margins in the shoulder,elbow,and temporomandibular joints.However,in our case,its application on an abdominal surgical wound delayed its primary healing intention.The valuable lesson was that,when choosing a treatment method for HO based on available research data,its location must be considered.CONCLUSION Complete excision should be the priority treatment option for symptomatic HO along the laparotomy scar.Bone wax application is not recommended.Core Tip:Heterotopic ossification(HO)represents all types of extraskeletal ossification,and occurs in various areas,including the skin,muscle,and joints.There are some suggested treatment and preventive approaches for symptomatic HO,which include surgical excision and preventive measures such as postoperative radiotherapy,oral nonsteroidal anti-inflam-matory drugs,and topical sealants(bone wax).However,these recommendations are based on personal experiences limited to HO in certain locations.It is important to individualize our treatment approaches depending on its location.For symptomatic HO along the laparotomy scar,complete surgical excision should be the priority treatment option,and bone wax application is not recommended.展开更多
BACKGROUND Heterotopic mesenteric ossification(HMO)is a clinically rare condition characterized by the formation of bone tissue in the mesentery.The worldwide reporting of such cases is limited to just over 70 instanc...BACKGROUND Heterotopic mesenteric ossification(HMO)is a clinically rare condition characterized by the formation of bone tissue in the mesentery.The worldwide reporting of such cases is limited to just over 70 instances in the medical literature.The etiology of HMO remains unclear,but the disease is possibly induced by mechanical trauma,ischemia,or intra-left lower quadrant abdominal infection,leading to the differentiation of mesenchymal stem cells into osteoblasts.Here,we present a rare case of HMO that occurred in a 34-year-old male,who presented with left lower quadrant abdominal pain.CASE SUMMARY We report the case of a 34-year-old male patient who presented with left lower abdominal pain following trauma to the left lower abdomen.He subsequently underwent surgical treatment,and the postoperative pathological diagnosis was HMO.CONCLUSION We believe that although there is limited literature and research on HMO,when patients with a history of trauma or surgery to the left lower abdomen present with corresponding imaging findings,clinicians should be vigilant in distinguishing this condition and promptly selecting appropriate diagnostic and therapeutic interventions.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
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
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
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
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
BACKGROUND Neurogenic heterotopic ossification is an acquired serious complication described in patients with central nervous system disorders and defined by bone formation in non-osseous tissue.CASE SUMMARY We presen...BACKGROUND Neurogenic heterotopic ossification is an acquired serious complication described in patients with central nervous system disorders and defined by bone formation in non-osseous tissue.CASE SUMMARY We present an unusual case of a 13-yr-old boy presenting with hip pain and severe gait impairment 5 mo after the diagnosis of hemiplegia following a spontaneous intracerebral haemorrhage.Computed tomography revealed bilateral heterotopic ossification of both the paretic and the non-paretic limbs,with entrapment of the sciatic nerve.The choice of surgical or nonsurgical management of such patients depends on the timing of diagnosis,the symptoms,and the extent of maturation of the ossified lesions.Surgical resection remains the only treatment with proven,evidence-based effectiveness.The choice of surgical approach largely depends on the location of the ossified lesions.CONCLUSION We believe the plane of dissection presented is a satisfactory option for resection of a posteromedial mass and sciatic nerve release.展开更多
Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due t...Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.展开更多
BACKGROUND Cervical disc arthroplasty(CDA)is an alternative treatment to traditional interbody fusion that maintains postoperative cervical spine mobility.However,the CDA postoperative period is impacted by osteolysis...BACKGROUND Cervical disc arthroplasty(CDA)is an alternative treatment to traditional interbody fusion that maintains postoperative cervical spine mobility.However,the CDA postoperative period is impacted by osteolysis,subsidence,metallosis,or heterotopic ossification(HO).We report a case of severe HO in a seronegative spondyloarthritis patient after cervical Bryan disc arthroplasty.CASE SUMMARY A 34-year-old man received hybrid surgery for C4-C5 and C5-C6 arthroplasty with Bryan discs and C6-C7 arthrodesis with polyetheretherketone cage due to traumatic herniation of the intervertebral disc(HIVD).After four years,cervical spine radiographs revealed severe HO around the Bryan discs over the C4-C5 and C5-C6 levels.The magnetic resonance image revealed HIVD over the C3-C4 level with spinal cord compression.Seronegative spondyloarthritis was diagnosed after consultation with a rheumatologist.A second CDA for the adjacent segment disease HIVD with Baguera C disc over the C3-C4 level achieved an excellent outcome.CONCLUSION Minimizing intraoperative tissue trauma and achieving postoperative interbody stability avoid soft tissue traction to prevent HO formation after CDA.展开更多
Background: Radiation therapy prophylaxis for heterotopic ossification is well-established for the hip, either pre or post-operatively. There is limited data for this treatment in non-hip sites. We report our institut...Background: Radiation therapy prophylaxis for heterotopic ossification is well-established for the hip, either pre or post-operatively. There is limited data for this treatment in non-hip sites. We report our institution’s experience. Methods: From October 2004 to August 2015, a total of 39 non-hip sites in 38 patients were treated with prophylactic radiation therapy for heterotopic ossification at our institution. An IRB approved retrospective review was performed. There were 15 patients who received treatments to the elbow, 13 to the knee (1 bilateral for a total of 14 knees), and 10 to other sites (leg stump (2), pubic symphysis (2), femur (1), foot (1), humerus stump (1), abdominal wall (1), shoulder (1), thigh (1)). All but 1 patient were treated with a single fraction treatment with 700 or 800 cGy. One patient received 2000 cGy in 10 fractions to the abdominal wall for heterotopic ossification extending from the xiphoid process. Results: Fifteen patients underwent treatment to the elbow with a median follow-up of 5 months (0 - 99). Median age for this group was 50 years (37 - 69). Nine (60.0%) patients had evidence of heterotopic ossification prior to surgery. All (100%) of the elbow patients were free from recurrence at last follow-up. There were no acute or late toxicities noted. For treatment to the knee, there were 4 (28.6%) recurrences, all in cases where there were pre-operative heterotopic ossification. There were two other recurrences in the non-hip, elbow or knee sites: one patient who received radiation therapy to the abdominal wall and one patient who underwent treatment to the thigh. Conclusions: Prophylactic radiation therapy with 700 cGy or 800 cGy in 1 fraction either before or after surgery remains a safe and effective treatment for both hip and most non-hip sites. Fractionated treatment may be used for larger treatment fields, however experience is limited.展开更多
Heterotopic ossification (HO) is the abnormal, non-neoplastic presence of lamellar bone in soft tissue. The ectopic formation of lamellar bone in non-osseus tissues secondary to traumatic injuries of the spinal cord o...Heterotopic ossification (HO) is the abnormal, non-neoplastic presence of lamellar bone in soft tissue. The ectopic formation of lamellar bone in non-osseus tissues secondary to traumatic injuries of the spinal cord or the brain is defined as Neurogenic HO. The pathophysiology of HO is not clear. But several theories like overactive humoral mechanisms after fracture healing, imbalance of pro-osteoinductive and anti-osteoinductive mediators located on the soft tissues and gene mutations in such as bone morphogenetic proteins-4 (BMP-4) are proposed. Casualty factors leading to increased risk of HO include older age, blast mechanism of injury, location of injury and traumatic brain injury. The aim of this paper is to demonstrate a case of HO located in the brain without history of trauma or any other risk factors.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
The endochondral ossification of hindlimb is essential to a bird’s ability to stand,walk and fly.Most hindlimb is ossified in the embryos before hatching in precocial birds.However,the molecular mechanisms of hindlim...The endochondral ossification of hindlimb is essential to a bird’s ability to stand,walk and fly.Most hindlimb is ossified in the embryos before hatching in precocial birds.However,the molecular mechanisms of hindlimb ossification in birds is still unclear.Therefore,we tried to examine the process of hindlimb ossification and its molecular regulation by using an animal model—Japanese Quail(Coturnix japonica).We selected four critical stages(Embryo Day:E6,E8,E12 and E16) of skeletal development of embryonic quails for hindlimb skeleton staining to show the process of endochondral ossification and to examine the molecular regulation of endochondral osteogenesis by RNA-Seq analysis.The results showed that ossification became increased with embryonic development and most hindlimb was ossified before hatching.RNA-Seq analysis revealed that various signaling pathways were involved with endochondral ossification with thyroid hormone signaling and WNT signaling pathway particularly enriched.Moreover,the expression levels of 42 genes were continuously upregulated and 14 genes were continuously downregulated from E6 to E16.The present study might provide new insights into complex molecular mechanisms in regulation of endochondral ossification.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
After reconstructing the anterior cruciate ligament(ACL),unsatisfactory bone tendon interface healing may often induce tunnel enlargement at the early healing stage.With good biological features and high formability,M...After reconstructing the anterior cruciate ligament(ACL),unsatisfactory bone tendon interface healing may often induce tunnel enlargement at the early healing stage.With good biological features and high formability,Magnesium-Zinc-Gadolinium(ZG21)wires are developed to bunch the tendon graft for matching the bone tunnel during transplantation.Microstructure,tensile strength,degradation,and cytotoxicity of ZG21 wire are evaluated.The rabbit model is used for assessing the biological effects of ZG21 wire by Micro-CT,histology,and mechanical test.The SEM/EDS,immunochemistry,and in vitro assessments are performed to investigate the underlying mechanism.Material tests demonstrate the high formability of ZG21 wire as surgical suture.Micro-CT shows ZG21 wire degradation accelerates tunnel bone formation,and histologically with earlier and more fibrocartilage regeneration at the healing interface.The mechanical test shows higher ultimate load in the ZG21 group.The SEM/EDS presents ZG21 wire degradation triggered calcium phosphate(Ca-P)deposition.IHC results demonstrate upregulation of Wnt3a,BMP2,and VEGF at the early phase and TGFβ3 and Type II collagen at the late phase of healing.In vitro tests also confirmed the Ca-P in the metal extract could elevate the expression of Wnt3a,βcatenin,ocn and opn to stimulate osteogenesis.Ex vivo tests of clinical samples indicated suturing with ZG21 wire did not weaken the ultimate loading of human tendon tissue.In conclusion,the ZG21 wire is feasible for tendon graft bunching.Its degradation products accelerated intra-tunnel endochondral ossification at the early healing stage and therefore enhanced bone-tendon interface healing in ACL reconstruction.展开更多
Background:Ossification of the posterior longitudinal ligament(OPLL)is a prevalent condition in orthopedics.While death-associated protein kinase 2(DAPK2)is known to play roles in cellular apoptosis and autophagy,its ...Background:Ossification of the posterior longitudinal ligament(OPLL)is a prevalent condition in orthopedics.While death-associated protein kinase 2(DAPK2)is known to play roles in cellular apoptosis and autophagy,its specific contributions to the advancement of OPLL are not well understood.Methods:Ligament fibroblasts were harvested from patients diagnosed with OPLL.Techniques such as real-time reverse transcriptasepolymerase chain reaction(RT-qPCR)and Western blot analysis were employed to assess DAPK2 levels in both ligament tissues and cultured fibroblasts.The extent of osteogenic differentiation in these cells was evaluated using an alizarin red S(ARS)staining.Additionally,the expression of ossification markers and autophagy markers was quantified.The autophagic activity was further analyzed through LC3 immunofluorescence and transmission electron microscopy(TEM).An in vivo heterotopic bone formation assay was conducted in mice to assess the role of DAPK2 in ossification.Results:Elevated DAPK2 expression was confirmed in both OPLL patient tissues and derived fibroblasts,in contrast to non-OPLL controls.Silencing of DAPK2 significantly curtailed osteogenic differentiation and autophagy in these fibroblasts,evidenced by decreased levels of LC3,and Beclin1,and reduced autophagosome formation.Additionally,DAPK2 was found to inhibit the mechanistic target of the rapamycin complex 1(mTORC1)complex’s activity.In vivo studies demonstrated that DAPK2 facilitates ossification,and this effect could be counteracted by the mTORC1 inhibitor rapamycin.Conclusion:DAPK2 enhances autophagy and osteogenic processes in OPLL through modulation of the mTORC1 pathway.展开更多
We present the case of a 64-year-old man with cervical ossification of the posterior longitudinal ligament (OPLL) experiencing chronic neck pain and radiculopathy for 6 months. A catheter-assisted interlaminar Cervica...We present the case of a 64-year-old man with cervical ossification of the posterior longitudinal ligament (OPLL) experiencing chronic neck pain and radiculopathy for 6 months. A catheter-assisted interlaminar Cervical Epidural Steroid Injection (CESI) was performed under fluoroscopic guidance, targeting the affected C2-C6 levels. Significant improvement was observed after this procedure, with decreased pain scores (visual analogue scale (VAS) 8 to 2) and improved mobility. This technique not only enhances the effectiveness of CESI but also reduces the likelihood of complications such as stroke or epidural hematoma and thus provides an alternative treatment option for patients with multiple stenotic levels who are unsuitable for surgery or are unresponsive to conservative therapy such as medication or physical therapy.展开更多
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.
基金Supported by Scientific research project of Hunan Education Department,No.21B0075Science project of Hunan Provincial Health Commission,No.B2015-82。
文摘BACKGROUND Heterotopic ossification(HO)refers to the formation of new bone in non-skeletal tissues such as muscles,tendons or other soft tissues.Severe muscle and soft tissue injury often lead to the formation of HO.However,anterior HO of the ankle is rarely reported.CASE SUMMARY We report a patient with massive HO in front of the ankle joint for 23 years.In 1998,the patient was injured by a falling object on the right lower extremity,which gradually formed a massive heterotopic bone change in the right calf and dorsum of the foot.The patient did not develop gradual ankle function limitations until nearly 36 mo ago,and underwent resection of HO.Even after 23 years and resection of HO,the ankle joint was still able to move.CONCLUSION It is recommended that the orthopedist should be aware of HO and distinguish it from bone tumor.
文摘BACKGROUND Heterotopic ossification(HO)represents all types of extraskeletal ossification in the body.It occurs in various areas,including the skin,subcutaneous tissue,muscle,and joints.Surgical excision is recommended for symptomatic HO.Postoperative radiotherapy,oral nonsteroidal anti-inflammatory drugs,and topical sealants,such as bone wax,have been recommended as preventive measures.As HO is rare in occurrence,these recommendations are based on personal experiences,and there is a lack of information on individualized treatments depending on its location.CASE SUMMARY A 62-year-old male was admitted for symptomatic HO along a laparotomy scar.Surgical excision was performed for an 11 cm-sized ossification originating from the xiphoid process,and bone wax was applied to the excisional margin.However,the surgical wound failed to heal.After several weeks of saline-soaked gauze dressing,delayed wound closure was performed.The patient was finally discharged eight weeks after the excision.Because HO can occur in various areas of the body,a treatment strategy that may be effective for some may not be for others.Bone wax has been used as a topical sealant over excisional margins in the shoulder,elbow,and temporomandibular joints.However,in our case,its application on an abdominal surgical wound delayed its primary healing intention.The valuable lesson was that,when choosing a treatment method for HO based on available research data,its location must be considered.CONCLUSION Complete excision should be the priority treatment option for symptomatic HO along the laparotomy scar.Bone wax application is not recommended.Core Tip:Heterotopic ossification(HO)represents all types of extraskeletal ossification,and occurs in various areas,including the skin,muscle,and joints.There are some suggested treatment and preventive approaches for symptomatic HO,which include surgical excision and preventive measures such as postoperative radiotherapy,oral nonsteroidal anti-inflam-matory drugs,and topical sealants(bone wax).However,these recommendations are based on personal experiences limited to HO in certain locations.It is important to individualize our treatment approaches depending on its location.For symptomatic HO along the laparotomy scar,complete surgical excision should be the priority treatment option,and bone wax application is not recommended.
基金Supported by Natural Science Foundation of Fujian Province,China No.2021J01545Natural Science Foundation of Zhangzhou City,Fujian Province,China No.ZZ2021J25.
文摘BACKGROUND Heterotopic mesenteric ossification(HMO)is a clinically rare condition characterized by the formation of bone tissue in the mesentery.The worldwide reporting of such cases is limited to just over 70 instances in the medical literature.The etiology of HMO remains unclear,but the disease is possibly induced by mechanical trauma,ischemia,or intra-left lower quadrant abdominal infection,leading to the differentiation of mesenchymal stem cells into osteoblasts.Here,we present a rare case of HMO that occurred in a 34-year-old male,who presented with left lower quadrant abdominal pain.CASE SUMMARY We report the case of a 34-year-old male patient who presented with left lower abdominal pain following trauma to the left lower abdomen.He subsequently underwent surgical treatment,and the postoperative pathological diagnosis was HMO.CONCLUSION We believe that although there is limited literature and research on HMO,when patients with a history of trauma or surgery to the left lower abdomen present with corresponding imaging findings,clinicians should be vigilant in distinguishing this condition and promptly selecting appropriate diagnostic and therapeutic interventions.
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.
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.
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.
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.
文摘BACKGROUND Neurogenic heterotopic ossification is an acquired serious complication described in patients with central nervous system disorders and defined by bone formation in non-osseous tissue.CASE SUMMARY We present an unusual case of a 13-yr-old boy presenting with hip pain and severe gait impairment 5 mo after the diagnosis of hemiplegia following a spontaneous intracerebral haemorrhage.Computed tomography revealed bilateral heterotopic ossification of both the paretic and the non-paretic limbs,with entrapment of the sciatic nerve.The choice of surgical or nonsurgical management of such patients depends on the timing of diagnosis,the symptoms,and the extent of maturation of the ossified lesions.Surgical resection remains the only treatment with proven,evidence-based effectiveness.The choice of surgical approach largely depends on the location of the ossified lesions.CONCLUSION We believe the plane of dissection presented is a satisfactory option for resection of a posteromedial mass and sciatic nerve release.
基金supported by the National Key R&D Program of China(2017YFA0104900)the National Natural Science Foundation of China(31830029,81501937 and 81522029)the Fundamental Research Funds for the Central Universities(K20200099).
文摘Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.
文摘BACKGROUND Cervical disc arthroplasty(CDA)is an alternative treatment to traditional interbody fusion that maintains postoperative cervical spine mobility.However,the CDA postoperative period is impacted by osteolysis,subsidence,metallosis,or heterotopic ossification(HO).We report a case of severe HO in a seronegative spondyloarthritis patient after cervical Bryan disc arthroplasty.CASE SUMMARY A 34-year-old man received hybrid surgery for C4-C5 and C5-C6 arthroplasty with Bryan discs and C6-C7 arthrodesis with polyetheretherketone cage due to traumatic herniation of the intervertebral disc(HIVD).After four years,cervical spine radiographs revealed severe HO around the Bryan discs over the C4-C5 and C5-C6 levels.The magnetic resonance image revealed HIVD over the C3-C4 level with spinal cord compression.Seronegative spondyloarthritis was diagnosed after consultation with a rheumatologist.A second CDA for the adjacent segment disease HIVD with Baguera C disc over the C3-C4 level achieved an excellent outcome.CONCLUSION Minimizing intraoperative tissue trauma and achieving postoperative interbody stability avoid soft tissue traction to prevent HO formation after CDA.
文摘Background: Radiation therapy prophylaxis for heterotopic ossification is well-established for the hip, either pre or post-operatively. There is limited data for this treatment in non-hip sites. We report our institution’s experience. Methods: From October 2004 to August 2015, a total of 39 non-hip sites in 38 patients were treated with prophylactic radiation therapy for heterotopic ossification at our institution. An IRB approved retrospective review was performed. There were 15 patients who received treatments to the elbow, 13 to the knee (1 bilateral for a total of 14 knees), and 10 to other sites (leg stump (2), pubic symphysis (2), femur (1), foot (1), humerus stump (1), abdominal wall (1), shoulder (1), thigh (1)). All but 1 patient were treated with a single fraction treatment with 700 or 800 cGy. One patient received 2000 cGy in 10 fractions to the abdominal wall for heterotopic ossification extending from the xiphoid process. Results: Fifteen patients underwent treatment to the elbow with a median follow-up of 5 months (0 - 99). Median age for this group was 50 years (37 - 69). Nine (60.0%) patients had evidence of heterotopic ossification prior to surgery. All (100%) of the elbow patients were free from recurrence at last follow-up. There were no acute or late toxicities noted. For treatment to the knee, there were 4 (28.6%) recurrences, all in cases where there were pre-operative heterotopic ossification. There were two other recurrences in the non-hip, elbow or knee sites: one patient who received radiation therapy to the abdominal wall and one patient who underwent treatment to the thigh. Conclusions: Prophylactic radiation therapy with 700 cGy or 800 cGy in 1 fraction either before or after surgery remains a safe and effective treatment for both hip and most non-hip sites. Fractionated treatment may be used for larger treatment fields, however experience is limited.
文摘Heterotopic ossification (HO) is the abnormal, non-neoplastic presence of lamellar bone in soft tissue. The ectopic formation of lamellar bone in non-osseus tissues secondary to traumatic injuries of the spinal cord or the brain is defined as Neurogenic HO. The pathophysiology of HO is not clear. But several theories like overactive humoral mechanisms after fracture healing, imbalance of pro-osteoinductive and anti-osteoinductive mediators located on the soft tissues and gene mutations in such as bone morphogenetic proteins-4 (BMP-4) are proposed. Casualty factors leading to increased risk of HO include older age, blast mechanism of injury, location of injury and traumatic brain injury. The aim of this paper is to demonstrate a case of HO located in the brain without history of trauma or any other risk factors.
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supported by the National Natural Science Foundationof China (No. 33372201)。
文摘The endochondral ossification of hindlimb is essential to a bird’s ability to stand,walk and fly.Most hindlimb is ossified in the embryos before hatching in precocial birds.However,the molecular mechanisms of hindlimb ossification in birds is still unclear.Therefore,we tried to examine the process of hindlimb ossification and its molecular regulation by using an animal model—Japanese Quail(Coturnix japonica).We selected four critical stages(Embryo Day:E6,E8,E12 and E16) of skeletal development of embryonic quails for hindlimb skeleton staining to show the process of endochondral ossification and to examine the molecular regulation of endochondral osteogenesis by RNA-Seq analysis.The results showed that ossification became increased with embryonic development and most hindlimb was ossified before hatching.RNA-Seq analysis revealed that various signaling pathways were involved with endochondral ossification with thyroid hormone signaling and WNT signaling pathway particularly enriched.Moreover,the expression levels of 42 genes were continuously upregulated and 14 genes were continuously downregulated from E6 to E16.The present study might provide new insights into complex molecular mechanisms in regulation of endochondral ossification.
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.
基金Theme-based research scheme of Hong Kong Research Grant Council(RGC Ref:T13-402/17-N)National Natural Science Foundation of China(No.U1804251)。
文摘After reconstructing the anterior cruciate ligament(ACL),unsatisfactory bone tendon interface healing may often induce tunnel enlargement at the early healing stage.With good biological features and high formability,Magnesium-Zinc-Gadolinium(ZG21)wires are developed to bunch the tendon graft for matching the bone tunnel during transplantation.Microstructure,tensile strength,degradation,and cytotoxicity of ZG21 wire are evaluated.The rabbit model is used for assessing the biological effects of ZG21 wire by Micro-CT,histology,and mechanical test.The SEM/EDS,immunochemistry,and in vitro assessments are performed to investigate the underlying mechanism.Material tests demonstrate the high formability of ZG21 wire as surgical suture.Micro-CT shows ZG21 wire degradation accelerates tunnel bone formation,and histologically with earlier and more fibrocartilage regeneration at the healing interface.The mechanical test shows higher ultimate load in the ZG21 group.The SEM/EDS presents ZG21 wire degradation triggered calcium phosphate(Ca-P)deposition.IHC results demonstrate upregulation of Wnt3a,BMP2,and VEGF at the early phase and TGFβ3 and Type II collagen at the late phase of healing.In vitro tests also confirmed the Ca-P in the metal extract could elevate the expression of Wnt3a,βcatenin,ocn and opn to stimulate osteogenesis.Ex vivo tests of clinical samples indicated suturing with ZG21 wire did not weaken the ultimate loading of human tendon tissue.In conclusion,the ZG21 wire is feasible for tendon graft bunching.Its degradation products accelerated intra-tunnel endochondral ossification at the early healing stage and therefore enhanced bone-tendon interface healing in ACL reconstruction.
基金This research received funding from the Natural Science Foundation of Shanghai(Grant No.20ZR1457600)the School-Level Basic Medical Project of Naval Medical University(Grant No.2021MS13).
文摘Background:Ossification of the posterior longitudinal ligament(OPLL)is a prevalent condition in orthopedics.While death-associated protein kinase 2(DAPK2)is known to play roles in cellular apoptosis and autophagy,its specific contributions to the advancement of OPLL are not well understood.Methods:Ligament fibroblasts were harvested from patients diagnosed with OPLL.Techniques such as real-time reverse transcriptasepolymerase chain reaction(RT-qPCR)and Western blot analysis were employed to assess DAPK2 levels in both ligament tissues and cultured fibroblasts.The extent of osteogenic differentiation in these cells was evaluated using an alizarin red S(ARS)staining.Additionally,the expression of ossification markers and autophagy markers was quantified.The autophagic activity was further analyzed through LC3 immunofluorescence and transmission electron microscopy(TEM).An in vivo heterotopic bone formation assay was conducted in mice to assess the role of DAPK2 in ossification.Results:Elevated DAPK2 expression was confirmed in both OPLL patient tissues and derived fibroblasts,in contrast to non-OPLL controls.Silencing of DAPK2 significantly curtailed osteogenic differentiation and autophagy in these fibroblasts,evidenced by decreased levels of LC3,and Beclin1,and reduced autophagosome formation.Additionally,DAPK2 was found to inhibit the mechanistic target of the rapamycin complex 1(mTORC1)complex’s activity.In vivo studies demonstrated that DAPK2 facilitates ossification,and this effect could be counteracted by the mTORC1 inhibitor rapamycin.Conclusion:DAPK2 enhances autophagy and osteogenic processes in OPLL through modulation of the mTORC1 pathway.
文摘We present the case of a 64-year-old man with cervical ossification of the posterior longitudinal ligament (OPLL) experiencing chronic neck pain and radiculopathy for 6 months. A catheter-assisted interlaminar Cervical Epidural Steroid Injection (CESI) was performed under fluoroscopic guidance, targeting the affected C2-C6 levels. Significant improvement was observed after this procedure, with decreased pain scores (visual analogue scale (VAS) 8 to 2) and improved mobility. This technique not only enhances the effectiveness of CESI but also reduces the likelihood of complications such as stroke or epidural hematoma and thus provides an alternative treatment option for patients with multiple stenotic levels who are unsuitable for surgery or are unresponsive to conservative therapy such as medication or physical therapy.