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Cell Reports Apr 2024Heterotopic ossification (HO) is a challenging condition that occurs after musculoskeletal injury and is characterized by the formation of bone in non-skeletal tissues....
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.
Topics: Animals; Ossification, Heterotopic; Vascular Endothelial Growth Factor C; Lymphangiogenesis; Mice; Mesenchymal Stem Cells; Lymphatic Vessels; Cell Differentiation; Tenocytes; Osteogenesis; Haploinsufficiency; Mice, Inbred C57BL; Disease Models, Animal; Male
PubMed: 38573853
DOI: 10.1016/j.celrep.2024.114049 -
Orthopaedics & Traumatology, Surgery &... Feb 2018Neurogenic heterotopic ossification of the hip is secondary to neurologic lesions such as cranial trauma, stroke, medullary injury or cerebral anoxia. We shall not deal... (Review)
Review
Neurogenic heterotopic ossification of the hip is secondary to neurologic lesions such as cranial trauma, stroke, medullary injury or cerebral anoxia. We shall not deal here with the other etiologies of heterotopic ossification. There are numerous locations within the hip, depending on etiology and relations with adjacent neurovascular structures are sometimes close. Preoperative work-up should include contrast-enhanced CT; scintigraphy is non-contributive. Indications for surgery are decided in a multidisciplinary team meeting, with a contract laying out expected functional gain. It is this contract that determines the extent of resection, without seeking complete resection, which would incur an increased risk of complications. The surgical approach and resection strategy depend on lesion location and any resulting neurovascular compression. The most common complications are infection and postoperative hematoma. No adjuvant treatments have demonstrated efficacy against recurrence.
Topics: Craniocerebral Trauma; Hip; Humans; Hypoxia, Brain; Ossification, Heterotopic; Stroke
PubMed: 29174871
DOI: 10.1016/j.otsr.2017.04.015 -
Bioscience Reports Aug 2019Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and... (Review)
Review
Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.
Topics: Activins; Animals; Humans; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction
PubMed: 31341010
DOI: 10.1042/BSR20190377 -
Orthopaedic Surgery May 2015Thoracic ossification of the ligamentum flavum (TOLF) is the most common cause for thoracic spinal stenosis. TOLF is usually complicated by thoracic disc herniation,... (Review)
Review
Thoracic ossification of the ligamentum flavum (TOLF) is the most common cause for thoracic spinal stenosis. TOLF is usually complicated by thoracic disc herniation, ossification of the posterior longitudinal ligament and degenerative spinal diseases such as cervical spondylosis and lumbar spinal stenosis, and the ossification also usually has a discontinuous or continuous multi-segment distribution. The resultant superposition of several symptoms makes the clinical manifestations complex. Currently, the diagnosis of TOLF depends mainly on the patient's symptoms, physical examination and thoracic CT and MRI examinations. Identification of the location of TOLF depends more on the doctor's subjective judgement. Diagnostic problems are related to the specific region and level of surgical decompression: if the extent of decompression is insufficient, the treatment is inadequate, resulting in residual symptoms. Obversely, unnecessary trauma and a various complications will occur if the decompression is too extensive. Hence, the clinical features and process of diagnosis, especially the means of identifying the location, still require further improvement. It is necessary to establish a simple and accurate means of identifying the segment of TOLF that is responsible for the neurologic deficit: a number of spinal surgeons have been working hard on this. This article will provided an overview of the clinical features of TOLF and the related problems of clinical identification of the location of the segment causing the neurological deficit. The relationship between the imaging manifestations and clinical characteristics still need to be explored with the aim of establishing a simple and precise method for determining precisely whether TOLF is related to spinal cord injury or not, thus reducing surgical trauma and achieving an optimal prognosis.
Topics: Humans; Ligamentum Flavum; Ossification, Heterotopic; Spinal Stenosis; Thoracic Vertebrae
PubMed: 26033987
DOI: 10.1111/os.12165 -
Nature Communications Apr 2023Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in...
Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.
Topics: Female; Humans; Connective Tissue; Hedgehog Proteins; Ossification, Heterotopic; Signal Transduction; Transforming Growth Factor beta
PubMed: 37041138
DOI: 10.1038/s41467-023-37585-8 -
Seminars in Cell & Developmental Biology Jan 2016The progressive transformation of one organ system into another is a fundamental signature of fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of... (Review)
Review
The progressive transformation of one organ system into another is a fundamental signature of fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of extraskeletal bone formation in humans. In all affected individuals, FOP is caused by heterozygous missense gain-of-function mutations in Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor. Loss of autoinhibition of the mutant receptor (mACVR1) results in dysregulated BMP pathway signaling, and is necessary for the myriad developmental features of FOP, but does not appear sufficient to induce the episodic flare-ups that lead to disabling post-natal heterotopic endochondral ossification (HEO) and that are a hallmark of the disease. Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system. Recent studies implicate canonical and non-canonical TGFβ/BMP family ligands in the amplification of mACVR1 signaling leading to the formation of FOP lesions and resultant HEO. BMP and Activin ligands that stimulate mACVR1 signaling also have critical regulatory functions in the immune system. Cross-talk between the morphogenetic and immunological pathways that regulate tissue maintenance and wound healing identifies potential robust therapeutic targets for FOP. Here we review current evidence for an immunological trigger for flare-ups and HEO in FOP, propose a working schema for the pathophysiology of observed phenomena, and highlight outstanding questions under investigation.
Topics: Activin Receptors, Type I; Activins; Animals; Bone Morphogenetic Proteins; Humans; Immunity, Innate; Mutation, Missense; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction
PubMed: 26706149
DOI: 10.1016/j.semcdb.2015.12.013 -
Stem Cell Research & Therapy Dec 2022Heterotopic ossification (HO) is the formation of bone in non-osseous tissues, such as skeletal muscles. The HO could have a genetic or a non-genetic (acquired)... (Review)
Review
Heterotopic ossification (HO) is the formation of bone in non-osseous tissues, such as skeletal muscles. The HO could have a genetic or a non-genetic (acquired) background, that is, it could be caused by musculoskeletal trauma, such as burns, fractures, joint arthroplasty (traumatic HO), or cerebral or spinal insult (neurogenetic HO). HO formation is caused by the differentiation of stem or progenitor cells induced by local or systemic imbalances. The main factors described so far in HO induction are TGFβ1, BMPs, activin A, oncostatin M, substance P, neurotrophin-3, and WNT. In addition, dysregulation of noncoding RNAs, such as microRNA or long noncoding RNA, homeostasis may play an important role in the development of HO. For example, decreased expression of miRNA-630, which is responsible for the endothelial-mesenchymal transition, was observed in HO patients. The reduced level of miRNA-421 in patients with humeral fracture was shown to be associated with overexpression of BMP2 and a higher rate of HO occurrence. Down-regulation of miRNA-203 increased the expression of runt-related transcription factor 2 (RUNX2), a crucial regulator of osteoblast differentiation. Thus, understanding the various functions of noncoding RNAs can reveal potential targets for the prevention or treatment of HO.
Topics: Humans; MicroRNAs; RNA, Long Noncoding; Ossification, Heterotopic; Osteogenesis; Cell Differentiation
PubMed: 36522666
DOI: 10.1186/s13287-022-03213-3 -
Journal of ISAKOS : Joint Disorders &... Dec 2023Heterotopic ossification (HO) is a known complication diagnosed following hip arthroscopy. (Review)
Review
INTRODUCTION
Heterotopic ossification (HO) is a known complication diagnosed following hip arthroscopy.
PURPOSE/HYPOTHESIS
This study sought to review the current literature on chemoprophylaxis for HO following hip arthroscopy and to describe what agents and doses are being utilized.
STUDY DESIGN
Systematic Review.
METHODS
A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines on the use of chemoprophylactic medications for HO prevention following hip arthroscopy. Mechanical and radiation prophylaxis were not included in the current analysis.
RESULTS
A total of 203 studies were identified, of which 15 were included with 6463 patients. There was one randomized control trial (RCT) and 4 additional comparative studies. The most commonly utilized chemoprophylactic agents were the following: naproxen (n = 8), celecoxib (n = 3), indomethacin (n = 3), aspirin (n = 1), etoricoxib (n = 1), and etodolac (n = 1), and non-specific non-steroidal anti-inflammatory drugs (NSAIDs) (n = 1). Naproxen was either given at a dose of 500 mg once or twice daily for 2-4 weeks. RCTs and additional comparative studies showed significant HO prevention using chemoprophylactic agents following hip arthroscopy.
CONCLUSIONS
HO is a known and common complication following hip arthroscopy. The current systematic review found significant heterogeneity across the literature with respect to specific chemoprophylactic agents and their dosing regimens aimed to reduce the incidence and severity of HO following hip arthroscopy. Additionally, this review demonstrates that most studies that utilize chemoprophylaxis use NSAIDs with successful reduction in the incidence of HO.
LEVEL OF EVIDENCE
Level IV Evidence.
Topics: Humans; Naproxen; Arthroscopy; Postoperative Complications; Anti-Inflammatory Agents, Non-Steroidal; Ossification, Heterotopic; Chemoprevention
PubMed: 37619960
DOI: 10.1016/j.jisako.2023.08.005 -
Bone Apr 2018The majority of skeletal elements develop via endochondral ossification. This process starts with formation of mesenchymal cell condensations at prescribed sites and... (Review)
Review
The majority of skeletal elements develop via endochondral ossification. This process starts with formation of mesenchymal cell condensations at prescribed sites and times in the early embryo and is followed by chondrogenesis, growth plate cartilage maturation and hypertrophy, and replacement of cartilage with bone and marrow. This complex stepwise process is reactivated and recapitulated in physiologic conditions such as fracture repair, but can occur extraskeletally in pathologies including heterotopic ossification (HO), Ossification of the Posterior Longitudinal Ligament (OPLL) and Hereditary Multiple Exostoses (HME). One form of HO is common and is triggered by trauma, invasive surgeries or burns and is thus particularly common amongst severely wounded soldiers. There is also a congenital and very severe form of HO that occurs in children with Fibrodysplasia Ossificans Progressiva (FOP) and is driven by activating mutations in ACVR1 encoding the type I bone morphogenetic protein (BMP) receptor ALK2. Current treatments for acquired HO, including NSAIDs and local irradiation, are not always effective and can have side effects, and there is no effective treatment for HO in FOP. This review article describes the research path we took several years ago to develop a new and effective treatment for both congenital and acquired forms of HO and specifically, the testing of synthetic retinoid agonists to block the initial and critical chondrogenic step leading to HO onset and progression. We summarize studies with mouse models of injury-induced and congenital HO demonstrating the effectiveness and mode of action of the retinoid agonists, including Palovarotene. Our studies have provided the rationale for, directly led to, an ongoing phase 2 FDA clinical trial to test efficacy and safety of Palovarotene in FOP. Top-line results released a few months ago by the pharmaceutical sponsor Clementia are very encouraging. Given shared developmental pathways amongst pathologies of extraskeletal tissue formation, Palovarotene may also be effective in HME as preliminary in vitro data suggest.
Topics: Animals; Chondrogenesis; Humans; Myositis Ossificans; Ossification, Heterotopic; Osteogenesis; Retinoids; Signal Transduction
PubMed: 28826842
DOI: 10.1016/j.bone.2017.08.010 -
BMC Neurology Dec 2019The elongation of the styloid process is historically associated with two variants of the Eagle syndrome. The classic one, mainly characterized by pain and dysphagia,...
BACKGROUND
The elongation of the styloid process is historically associated with two variants of the Eagle syndrome. The classic one, mainly characterized by pain and dysphagia, and the carotid variant characterized by pain and sometimes by cerebral ischemia. We observed a further variant characterized by a styloid elongation coursing adjacent to the transverse process of C1, causing significant compression of the internal jugular vein.
METHODS
We reviewed all the cases of Eagle syndrome, including the jugular variant, admitted in our Hospital in the last six years. We compared symptomatology, associated comorbidities and imaging. Data were statistically analyzed.
RESULTS
Overall 23 patients were admitted to the Hospital for symptomatic elongation of the styloid process, 11 male and 12 females. The jugular variant of the Eagle syndrome is clinically delineated by significant differences, as compared to the classic variant and carotid variants. Headache was the more prominent symptom (p < .009) as well as a documented peri-mesencephalic hemorrhage was the more significant comorbidity (p < .0003). The group classic-carotid variant was characterized by ipsilateral pain respect to the jugular variant (p < .0003). CT angiography with venous phase extended to the neck veins and imaging reconstruction is highly recommended as imaging technique, complemented by color-Doppler ultrasound.
CONCLUSIONS
The elongation of the styloid process may have different paths which creates compression on the surrounding anatomical structures. There may be a possible association of jugular impingement by an elongated styloid process with symptoms.
TRIAL REGISTRATION
Protocol n°45-2013.
Topics: Adult; Female; Humans; Jugular Veins; Male; Middle Aged; Ossification, Heterotopic; Temporal Bone; Young Adult
PubMed: 31864313
DOI: 10.1186/s12883-019-1572-3