RESUMEN
In this study, the role of matrine, a component derived from traditional Chinese medicine, in modulating macrophage polarization and its effects on traumatic heterotopic ossification (HO) in mice was investigated. Traumatic HO is a pathological condition characterized by abnormal bone formation in nonskeletal tissues, often following severe trauma or surgery. The mechanisms underlying HO involve an enhanced inflammatory response and abnormal bone formation, with macrophages playing a crucial role. Our study demonstrated that matrine effectively inhibits the polarization of bone marrow-derived macrophages (BMDMs) toward the M2 phenotype, a subtype associated with anti-inflammatory processes and implicated in the progression of HO. Using in vitro assays, we showed that matrine suppresses key M2 markers and inhibits the MAPK signaling pathway in BMDMs. Furthermore, in vivo experiments revealed that matrine treatment significantly reduced HO formation in the Achilles tendons of mice and downregulated the expression of markers associated with M2 macrophages and the MAPK pathway. Our findings suggest that the ability of matrine to modulate macrophage polarization and inhibit the MAPK pathway has therapeutic potential for treating traumatic HO, providing a novel approach to managing this complex condition.
Asunto(s)
Alcaloides , Sistema de Señalización de MAP Quinasas , Macrófagos , Matrinas , Ratones Endogámicos C57BL , Osificación Heterotópica , Quinolizinas , Animales , Quinolizinas/farmacología , Alcaloides/farmacología , Osificación Heterotópica/tratamiento farmacológico , Osificación Heterotópica/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Polaridad Celular/efectos de los fármacosRESUMEN
Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 (ACVR1). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1Q207D, Sox2-Cre; Acvr1R206H/+ FOP mice and in burn tenotomy-treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO.
Asunto(s)
Receptores de Activinas Tipo I , Proteínas Morfogenéticas Óseas , Cilios , Proteínas Hedgehog , Miositis Osificante , Osificación Heterotópica , Transducción de Señal , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología , Cilios/metabolismo , Cilios/patología , Proteínas Hedgehog/metabolismo , Animales , Humanos , Proteínas Morfogenéticas Óseas/metabolismo , Receptores de Activinas Tipo I/metabolismo , Ratones , Miositis Osificante/metabolismo , Miositis Osificante/patología , Osteogénesis , Células Madre/metabolismoRESUMEN
Heterotopic ossification (HO) in tendons can lead to increased pain and poor tendon function. Although it is believed to share some characteristics with bone, the structural and elemental compositions of HO deposits have not been fully elucidated. This study utilizes a multimodal and multiscale approach for structural and elemental characterization of HO deposits in healing rat Achilles tendons at 3, 6, 12, 16, and 20 weeks post transection. The microscale tomography and scanning electron microscopy results indicate increased mineral density and Ca/P ratio in the maturing HO deposits (12 and 20 weeks), when compared to the early time points (3 weeks). Visually, the mature HO deposits present microstructures similar to calcaneal bone. Through synchrotron-based X-ray scattering and fluorescence, the hydroxyapatite (HA) crystallites are shorter along the c-axis and become larger in the ab-plane with increasing healing time, while the HA crystal thickness remains within the reference values for bone. At the mineralization boundary, the overlap between high levels of calcium and prominent crystallite formation was outlined by the presence of zinc and iron. In the mature HO deposits, the calcium content was highest, and zinc was more present internally, which could be indicative of HO deposit remodeling. This study emphasizes the structural and elemental similarities between the calcaneal bone and HO deposits.
Asunto(s)
Tendón Calcáneo , Osificación Heterotópica , Osificación Heterotópica/patología , Osificación Heterotópica/metabolismo , Animales , Tendón Calcáneo/patología , Tendón Calcáneo/química , Ratas , Cicatrización de Heridas , Ratas Sprague-Dawley , Durapatita/química , Durapatita/metabolismo , Masculino , Calcio/metabolismoRESUMEN
Heterotopic ossification (HO) refers to the formation of pathologic bone in nonskeletal tissues (including muscles, tendons or other soft tissues). HO typically occurs after a severe injury and can occur in any part of the body. HO lesions are highly vascularized. Angiogenesis, which is the formation of new blood vessels, plays an important role in the pathophysiology of HO. Surgical resection is considered an effective treatment for HO. However, it is difficult to completely remove new vessels, which can lead to the recurrence of HO and is often accompanied by significant problems such as intraoperative hemorrhage, demonstrating the important role of angiogenesis in HO. Here, we broadly summarize the current understanding of how angiogenesis contributes to HO; in particular, we focus on new insights into the cellular and signaling mechanisms underlying HO angiogenesis. We also review the development and current challenges associated with antiangiogenic therapy for HO.
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Neovascularización Patológica , Osificación Heterotópica , Osificación Heterotópica/patología , Osificación Heterotópica/fisiopatología , Humanos , Neovascularización Patológica/patología , Animales , Transducción de Señal , Inhibidores de la Angiogénesis/uso terapéutico , Relevancia Clínica , AngiogénesisRESUMEN
Heterotopic ossification (HO) occurs as a common complication after injury, while its risk factor and mechanism remain unclear, which restricts the development of pharmacological treatment. Clinical research suggests that diabetes mellitus (DM) patients are prone to developing HO in the tendon, but solid evidence and mechanical research are still needed. Here, we combined the clinical samples and the DM mice model to identify that disordered glycolipid metabolism aggravates the senescence of tendon-derived stem cells (TSCs) and promotes osteogenic differentiation. Then, combining the RNA-seq results of the aging tendon, we detected the abnormally activated autocrine CXCL13-CXCR5 axis in TSCs cultured in a high fat, high glucose (HFHG) environment and also in the aged tendon. Genetic inhibition of CXCL13 successfully alleviated HO formation in DM mice, providing a potential therapeutic target for suppressing HO formation in DM patients after trauma or surgery.
Asunto(s)
Quimiocina CXCL13 , Glucolípidos , Osificación Heterotópica , Osteogénesis , Receptores CXCR5 , Animales , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología , Osificación Heterotópica/genética , Ratones , Humanos , Quimiocina CXCL13/metabolismo , Quimiocina CXCL13/genética , Glucolípidos/metabolismo , Receptores CXCR5/metabolismo , Receptores CXCR5/genética , Células Madre/metabolismo , Tendones/metabolismo , Tendones/patología , Masculino , Ratones Endogámicos C57BL , Diferenciación Celular , Senescencia Celular , Transducción de Señal , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologíaRESUMEN
Neutrophils are emerging as an important player in skeletal muscle injury and repair. Neutrophils accumulate in injured tissue, thus releasing inflammatory factors, proteases and neutrophil extracellular traps (NETs) to clear muscle debris and pathogens when skeletal muscle is damaged. During the process of muscle repair, neutrophils can promote self-renewal and angiogenesis in satellite cells. When neutrophils are abnormally overactivated, neutrophils cause collagen deposition, functional impairment of satellite cells, and damage to the skeletal muscle vascular endothelium. Heterotopic ossification (HO) refers to abnormal bone formation in soft tissue. Skeletal muscle injury is one of the main causes of traumatic HO (tHO). Neutrophils play a pivotal role in activating BMPs and TGF-ß signals, thus promoting the differentiation of mesenchymal stem cells and progenitor cells into osteoblasts or osteoclasts to facilitate HO. Furthermore, NETs are specifically localized at the site of HO, thereby accelerating the formation of HO. Additionally, the overactivation of neutrophils contributes to the disruption of immune homeostasis to trigger HO. An understanding of the diverse roles of neutrophils will not only provide more information on the pathogenesis of skeletal muscle injury for repair and HO but also provides a foundation for the development of more efficacious treatment modalities for HO.
Asunto(s)
Inflamación , Músculo Esquelético , Neutrófilos , Osificación Heterotópica , Osteogénesis , Osificación Heterotópica/patología , Osificación Heterotópica/etiología , Osificación Heterotópica/inmunología , Osificación Heterotópica/metabolismo , Humanos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/inmunología , Animales , Inflamación/patología , Inflamación/inmunología , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunologíaAsunto(s)
Enfermedades del Cabello , Pilomatrixoma , Neoplasias Cutáneas , Humanos , Pilomatrixoma/patología , Neoplasias Cutáneas/patología , Enfermedades del Cabello/patología , Osificación Heterotópica/patología , Osificación Heterotópica/diagnóstico por imagen , Metaplasia/patología , Masculino , Femenino , BiopsiaRESUMEN
Heterotopic ossification (HO), the pathological formation of bone within soft tissues such as tendon and muscle, is a notable complication resulting from severe injury. While soft tissue injury is necessary for HO development, the specific molecular pathology responsible for trauma-induced HO remains a mystery. The previous study detected abnormal autophagy function in the early stages of tendon HO. Nevertheless, it remains to be determined whether autophagy governs the process of HO generation. Here, trauma-induced tendon HO model is used to investigate the relationship between autophagy and tendon calcification. In the early stages of tenotomy, it is observed that autophagic flux is significantly impaired and that blocking autophagic flux promoted the development of more rampant calcification. Moreover, Gt(ROSA)26sor transgenic mouse model experiments disclosed lysosomal acid dysfunction as chief reason behind impaired autophagic flux. Stimulating V-ATPase activity reinstated both lysosomal acid functioning and autophagic flux, thereby reversing tendon HO. This present study demonstrates that autophagy-lysosomal dysfunction triggers HO in the stages of tendon injury, with potential therapeutic targeting implications for HO.
Asunto(s)
Autofagia , Modelos Animales de Enfermedad , Lisosomas , Ratones Transgénicos , Osificación Heterotópica , Tendones , Osificación Heterotópica/metabolismo , Osificación Heterotópica/genética , Osificación Heterotópica/patología , Animales , Autofagia/fisiología , Ratones , Lisosomas/metabolismo , Tendones/metabolismo , Tendones/patología , Tendones/fisiopatología , Tenotomía/métodos , Masculino , Traumatismos de los Tendones/fisiopatología , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Ratones Endogámicos C57BLRESUMEN
Heterotopic ossification is the inappropriate formation of bone in soft tissues of the body. It can manifest spontaneously in rare genetic conditions or as a response to injury, known as acquired heterotopic ossification. There are several experimental models for studying acquired heterotopic ossification from different sources of damage. However, their tenuous mechanistic relevance to the human condition, invasive and laborious nature and/or lack of amenability to chemical and genetic screens, limit their utility. To address these limitations, we developed a simple zebrafish injury model that manifests heterotopic ossification with high penetrance in response to clinically emulating injuries, as observed in human myositis ossificans traumatica. Using this model, we defined the transcriptional response to trauma, identifying differentially regulated genes. Mutant analyses revealed that an increase in the activity of the potassium channel Kcnk5b potentiates injury response, whereas loss of function of the interleukin 11 receptor paralogue (Il11ra) resulted in a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signalling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra.
Asunto(s)
Osificación Heterotópica , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/genética , Osificación Heterotópica/genética , Osificación Heterotópica/patología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Regulación de la Expresión Génica , Envejecimiento/genética , Envejecimiento/patología , Heridas y Lesiones/complicaciones , Heridas y Lesiones/genética , Heridas y Lesiones/patología , Modelos Animales de Enfermedad , Mutación/genéticaRESUMEN
Calcification within pleomorphic adenomas of the lacrimal gland is well recognized but uncommon, being seen more readily in lacrimal gland carcinomas. Bony formation, ossification, in pleomorphic adenomas of the lacrimal glands is even rarer. Together with extensive sclerosis, or "coagulative necrosis," ossification and necrosis should alert the clinician to the risk of malignant transformation. However, both can mimic carcinomatous change, leading to misinterpretation of malignancy in an otherwise benign lacrimal gland neoplasm. We present 2 case reports of patients with clinically presumed pleomorphic adenomas of the lacrimal gland whose histopathology demonstrated lacrimal gland ossification and necrosis without features of malignancy or invasive disease.
Asunto(s)
Adenoma Pleomórfico , Neoplasias del Ojo , Enfermedades del Aparato Lagrimal , Aparato Lagrimal , Necrosis , Osificación Heterotópica , Humanos , Adenoma Pleomórfico/diagnóstico , Adenoma Pleomórfico/patología , Neoplasias del Ojo/diagnóstico , Neoplasias del Ojo/patología , Enfermedades del Aparato Lagrimal/diagnóstico , Enfermedades del Aparato Lagrimal/patología , Osificación Heterotópica/diagnóstico , Osificación Heterotópica/patología , Necrosis/diagnóstico , Aparato Lagrimal/patología , Aparato Lagrimal/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Diagnóstico Diferencial , AncianoRESUMEN
Stylocarotid artery syndrome (SAS) is a rare variant of Eagle's syndrome that may lead to transient ischemic attack or stroke. The underlying pathophysiological mechanism involves compression of the internal carotid artery by an elongated styloid process (ESP), potentially resulting in vascular occlusion or dissection. An ESP exceeding 2.5 cm is deemed elongated, with a length of 3.0 cm considered clinically significant. Although the prevalence of ESP ranges from 4.0% to 7.3%, symptomatic cases are rare; symptoms are present in only approximately 4.0% of individuals with an ESP. Unlike the typical symptoms of Eagle's syndrome, SAS may not cause pharyngeal discomfort, the sensation of a foreign body in the throat, dysphagia, or facial pain. This absence of characteristic symptoms as well as the development of central nervous system symptoms often leads patients to seek care from neurologists instead of otolaryngologists, increasing the likelihood of misdiagnosis or underdiagnosis. We herein report a unique case of ischemic stroke caused by SAS and present a literature review on cases of SAS-associated ischemic stroke published in the past decade. The reporting of this study conforms to the CARE guidelines.
Asunto(s)
Accidente Cerebrovascular Isquémico , Osificación Heterotópica , Hueso Temporal , Humanos , Masculino , Arteria Carótida Interna/anomalías , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/patología , Accidente Cerebrovascular Isquémico/etiología , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Osificación Heterotópica/complicaciones , Osificación Heterotópica/diagnóstico , Osificación Heterotópica/patología , Osificación Heterotópica/diagnóstico por imagen , Hueso Temporal/anomalías , Hueso Temporal/diagnóstico por imagen , Hueso Temporal/patología , AdultoAsunto(s)
Adenocarcinoma , Neoplasias de los Músculos , Osificación Heterotópica , Neoplasias del Recto , Medronato de Tecnecio Tc 99m , Humanos , Neoplasias del Recto/patología , Neoplasias del Recto/diagnóstico por imagen , Adenocarcinoma/secundario , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Osificación Heterotópica/diagnóstico por imagen , Osificación Heterotópica/etiología , Osificación Heterotópica/patología , Neoplasias de los Músculos/secundario , Neoplasias de los Músculos/diagnóstico por imagen , Masculino , Cintigrafía , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Hallazgos Incidentales , Radiofármacos , Persona de Mediana EdadRESUMEN
OBJECTIVE: Heterotopic ossification (HO), also known as ossifying myositis, is a condition that produces abnormal bone and cartilage tissue in the soft tissues. Hypoxia inducible factor lα (HIF-lα) regulates the expression of various genes, which is closely related to the promotion of bone formation, and Drosophila mothers against decapentaplegic protein (SMAD) mediates the signal transduction in the Bone morphogenetic protein (BMP) signaling pathway, which affects the function of osteoblasts and osteoclasts, and thus plays a key role in the regulation of bone remodeling. We aimed to investigate the mechanism by which HIF-1α induces osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in a hypoxic environment. METHODS: A cellular hypoxia model was constructed to verify the expression of HIF-1α, while alizarin red staining was performed to observe the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs). Alizarin red staining was used to analyze the late mineralization ability of the cells. Western blot analysis was performed to analyze the expression levels of osteogenesis-related factors OCN, OPN proteins as well as the pathway proteins BMP4, p-Smad1/5/8, and Smad1. We also constructed a rat model of ectopic bone formation, observed ectopic ossification by X-ray, and verified the success of the rat model by ELISA of HIF-1α. HE staining was used to observe the matrix and trabecular structure of bone, and Masson staining was used to observe the collagen and trabecular structure of bone. Immunohistochemistry analyzed the expression of OCN and OPN in ectopic bone tissues, and WB analyzed the expression of pathway proteins BMP4, p-Smad1/5/8 and Smad1 in ectopic bone tissues to verify the signaling pathway of ectopic bone formation. RESULTS: Our results indicate that hypoxic environment upregulates HIF-1a expression and activates BMP4/SMAD signaling pathway. This led to an increase in ALP content and enhanced expression of the osteogenesis-related factors OCN and OPN, resulting in enhanced osteogenic differentiation of BMSCs. The results of our in vivo experiments showed that rats inoculated with BMSCs overexpressing HIF-1α showed bony structures in tendon tissues, enhanced expression of the bone signaling pathways BMP4 and p-Smad1/5/8, and enhanced expression levels of the osteogenic-related factors OCN and OPN, resulting in the formation of ectopic bone. CONCLUSIONS: These data further suggest a novel mechanistic view that hypoxic bone marrow BMSCs activate the BMP4/SMAD pathway by up-regulating the expression level of HIF-1α, thereby promoting the secretion of osteogenic factors leading to ectopic bone formation.
Asunto(s)
Proteína Morfogenética Ósea 4 , Diferenciación Celular , Hipoxia de la Célula , Subunidad alfa del Factor 1 Inducible por Hipoxia , Células Madre Mesenquimatosas , Osteogénesis , Transducción de Señal , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratas , Proteína Morfogenética Ósea 4/metabolismo , Proteínas Smad/metabolismo , Ratas Sprague-Dawley , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología , MasculinoRESUMEN
The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the ACVR1/ALK2 gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO.
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Senescencia Celular , Miositis Osificante , Osificación Heterotópica , Humanos , Osificación Heterotópica/genética , Osificación Heterotópica/patología , Osificación Heterotópica/metabolismo , Senescencia Celular/genética , Miositis Osificante/genética , Miositis Osificante/patología , Miositis Osificante/metabolismo , Animales , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismoRESUMEN
The pathogenesis of trauma-induced heterotopic ossification (HO) in the tendon remains unclear, posing a challenging hurdle in treatment. Recognizing inflammation as the root cause of HO, anti-inflammatory agents hold promise for its management. Malvidin (MA), possessing anti-inflammatory properties, emerges as a potential agent to impede HO progression. This study aimed to investigate the effect of MA in treating trauma-induced HO and unravel its underlying mechanisms. Herein, the effectiveness of MA in preventing HO formation was assessed through local injection in a rat model. The potential mechanism underlying MA's treatment was investigated in the tendon-resident progenitor cells of tendon-derived stem cells (TDSCs), exploring its pathway in HO formation. The findings demonstrated that MA effectively hindered the osteogenic differentiation of TDSCs by inhibiting the mTORC1 signalling pathway, consequently impeding the progression of trauma-induced HO of Achilles tendon in rats. Specifically, MA facilitated the degradation of Rheb through the K48-linked ubiquitination-proteasome pathway by modulating USP4 and intercepted the interaction between Rheb and the mTORC1 complex, thus inhibiting the mTORC1 signalling pathway. Hence, MA presents itself as a promising candidate for treating trauma-induced HO in the Achilles tendon, acting by targeting Rheb for degradation through the ubiquitin-proteasome pathway.
Asunto(s)
Osificación Heterotópica , Complejo de la Endopetidasa Proteasomal , Proteína Homóloga de Ras Enriquecida en el Cerebro , Transducción de Señal , Ubiquitina , Animales , Ratas , Complejo de la Endopetidasa Proteasomal/metabolismo , Osificación Heterotópica/metabolismo , Osificación Heterotópica/etiología , Osificación Heterotópica/patología , Transducción de Señal/efectos de los fármacos , Proteína Homóloga de Ras Enriquecida en el Cerebro/metabolismo , Ubiquitina/metabolismo , Masculino , Osteogénesis/efectos de los fármacos , Tendones/metabolismo , Tendones/patología , Ratas Sprague-Dawley , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/complicaciones , Proteolisis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Tendón Calcáneo/metabolismo , Tendón Calcáneo/patología , Tendón Calcáneo/lesiones , Modelos Animales de Enfermedad , Ubiquitinación , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Células Madre/metabolismo , Células Madre/efectos de los fármacosRESUMEN
Heterotopic ossification (HO) is a challenging condition that occurs after musculoskeletal injury and is characterized by the formation of bone in non-skeletal tissues. While the effect of HO on blood vessels is well established, little is known about its impact on lymphatic vessels. Here, we use a mouse model of traumatic HO to investigate the relationship between HO and lymphatic vessels. We show that injury triggers lymphangiogenesis at the injury site, which is associated with elevated vascular endothelial growth factor C (VEGF-C) levels. Through single-cell transcriptomic analyses, we identify mesenchymal progenitor cells and tenocytes as sources of Vegfc. We demonstrate by lineage tracing that Vegfc-expressing cells undergo osteochondral differentiation and contribute to the formation of HO. Last, we show that Vegfc haploinsufficiency results in a nearly 50% reduction in lymphangiogenesis and HO formation. These findings shed light on the complex mechanisms underlying HO formation and its impact on lymphatic vessels.
Asunto(s)
Linfangiogénesis , Células Madre Mesenquimatosas , Osificación Heterotópica , Factor C de Crecimiento Endotelial Vascular , Animales , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología , Osificación Heterotópica/genética , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/genética , Ratones , Células Madre Mesenquimatosas/metabolismo , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patología , Diferenciación Celular , Tenocitos/metabolismo , Osteogénesis , Haploinsuficiencia , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , MasculinoRESUMEN
Heterotopic ossification (HO) comprises the abnormal formation of ectopic bone in extraskeletal soft tissue. The factors that initiate HO remain elusive. Herein, we found that calcified apoptotic vesicles (apoVs) led to increased calcification and stiffness of tendon extracellular matrix (ECM), which initiated M2 macrophage polarization and HO progression. Specifically, single-cell transcriptome analyses of different stages of HO revealed that calcified apoVs were primarily secreted by a PROCR+ fibroblast population. In addition, calcified apoVs enriched calcium by annexin channels, absorbed to collagen I via electrostatic interaction, and aggregated to produce calcifying nodules in the ECM, leading to tendon calcification and stiffening. More importantly, apoV-releasing inhibition or macrophage deletion both successfully reversed HO development. Thus, we are the first to identify calcified apoVs from PROCR+ fibroblasts as the initiating factor of HO, and might serve as the therapeutic target for inhibiting pathological calcification.
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Vesículas Extracelulares , Osificación Heterotópica , Humanos , Receptor de Proteína C Endotelial , Vesículas Extracelulares/patología , Osificación Heterotópica/patología , Osificación Heterotópica/terapia , Matriz Extracelular , FibroblastosRESUMEN
We present the case of a 61-year-old man who developed coronavirus disease 2019 (COVID-19) and died during treatment for relapsing polychondritis. The patient was intubated and treated with steroid pulse therapy, remdecivir, antibacterial agents, baricitinib, and tocilizumab. However, his respiratory condition worsened, and he died 108 days after disease onset. An autopsy revealed diffuse alveolar damage in the fibrotic phase in all lung lobes, diffuse pulmonary ossification, and cytomegalovirus-infected cells in the middle lobe of the right lung. We herein discuss the clinical features and pathological findings of COVID-19 in immunosuppressed patients.