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Current Opinion in Pharmacology Jun 2018Heterotopic ossification (HO) involves the formation and accumulation of extraskeletal bone tissue at the expense of local tissues including muscles and connective... (Review)
Review
Heterotopic ossification (HO) involves the formation and accumulation of extraskeletal bone tissue at the expense of local tissues including muscles and connective tissues. There are common forms of HO that are triggered by extensive trauma, burns and other bodily insults, and there are also rare congenital severe forms of HO that occur in children with Fibrodysplasia Ossificans Progressiva or Progressive Osseous Heteroplasia. Given that HO is often preceded by inflammation, current treatments usually involve anti-inflammatory drugs alone or in combination with local irradiation, but are not very effective. Recent studies have provided novel insights into the pathogenesis of acquired and genetic forms of HO and have used the information to conceive and test new and more specific therapies in animal models. In this review, I provide salient examples of these exciting and promising advances that are undoubtedly paving the way toward resolution of this debilitating and at times fatal disease.
Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Bone Diseases, Metabolic; Bone and Bones; Drug Discovery; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Myositis Ossificans; Ossification, Heterotopic; Osteogenesis; Phenotype; Skin Diseases, Genetic
PubMed: 29614433
DOI: 10.1016/j.coph.2018.03.007 -
Journal of ISAKOS : Joint Disorders &... Feb 2024In elbow stiffness, pre-operative assessments should identify the articular and peri-articular tissues involved and, more specifically, they should determine how...
In elbow stiffness, pre-operative assessments should identify the articular and peri-articular tissues involved and, more specifically, they should determine how preserved the articular surfaces and osteo-articular congruity are. We will focus on the most important conditions and tissue reactions after trauma in order to understand the causes of joint stiffness. A logical surgical planning is based upon a deep knowledge of the anatomical obstacles and of the associated lesions that the trauma provoked with. The peri-articular soft tissue contractures. The osteo-articular incongruity.
Topics: Humans; Elbow; Elbow Joint; Elbow Injuries; Treatment Outcome; Joint Dislocations; Arthritis; Ossification, Heterotopic
PubMed: 37879605
DOI: 10.1016/j.jisako.2023.10.009 -
Scientific Reports Dec 2019Heterotopic Ossification (HO) is a potential long-term complication in orthopaedic surgery. It is commonly classified according to the Brooker classification, which is...
Heterotopic Ossification (HO) is a potential long-term complication in orthopaedic surgery. It is commonly classified according to the Brooker classification, which is based on radiological findings. To our knowledge the correlation of histological features to the Brooker grade is unknown as is the association between HO and the indication for revision. The aim of this paper is to analyze the ossification grade of HO tissue in patients undergoing revision hip and knee arthroplasty and to propose a histologically based classification system for HO. We also assess the relationship between the grade of HO and the indication for revision (septic and aseptic revision). From January to May 2019 we collected 50 human HO samples from hip and knee revision arthroplasty cases. These tissue samples were double-blinded and sent for histopathological diagnostic. Based on these results, we developed a classification system for the progression of HO. The grade of ossification was based on three characteristics: Grade of heterotopic ossification (Grade 1-3), presence of necrosis (N0 or N1) and the presence of osteomyelitis (HOES-Score Type 1 to 5). Demographic data as well as surgical details and indication for surgery was prospectively collected from clinical records. Fifty tissue samples were harvested from 44 hips and 6 knee joints. Of these 33 exhibited Grade I ossifications (66%), followed by 11 Grade II (22%) and one Grade III (2%). Necrosis was noted in two tissue samples (4%) and 2 more had osteomyelitis findings according to HOES-Score. Six samples (12%) with radiologically suggestive of HO turned out to be wear-induced synovitis, SLIM Type 1. Of these cases 16 were septic (32%) and 34 aseptic (68%) revisions. Most of the HO tissue samples were classified as a low-grade. High-grade ossification-Score is rare. Higher grades of ossification seem to be associated with septic revision cases. Wear-induced synovitis potentially influences HO development. A histological scoring system for ossification grading can be derived from the data presented in this study.
Topics: Aged; Aged, 80 and over; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Disease Progression; Female; Hip Joint; Humans; Knee Joint; Male; Middle Aged; Necrosis; Ossification, Heterotopic; Osteomyelitis; Prospective Studies; Radiography; Severity of Illness Index; Synovitis
PubMed: 31804584
DOI: 10.1038/s41598-019-54986-2 -
Orthopaedic Surgery Sep 2022To evaluate the rate of increase in thickness and cross-section area (CSA) of the ossification in thoracic myelopathy with or without cervical and lumbar spinal ligament...
OBJECTIVE
To evaluate the rate of increase in thickness and cross-section area (CSA) of the ossification in thoracic myelopathy with or without cervical and lumbar spinal ligament ossification.
METHODS
A total of 24 patients with 170 segments (47 ligamentum flavum [OLF] and 123 cases of ossification of the posterior longitudinal ligament [OPLL]) of spinal ligament ossification between January 2012 and March 2019 at a single institution were retrospectively reviewed. Demographic data, classification of OPLL, Sato classification of OLF, pre- and postoperative neurological function and complications were recorded. The thickness and CSA at the segment of maximum compression were measured with Image J software on the axial CT image.
RESULTS
Twelve female and 12 male patients with thoracic myelopathy and spinal ligament ossification were enrolled in the study. The mean age of the patients was 54.0 ± 11.9 years with an average follow-up of 22.2 ± 23.5 months. Overall, the mean rate of progression in thickness and CSA was 1.2 ± 1.6 and 18.4 ± 50.6 mm /year, respectively. Being female, aging (≥45 years), and lower BMI (<28 kg/m ) predisposed patients to have faster ossification growth in thickness and CSA. The difference between the rate of OPLL and OLF progression in thickness and CSA was not significant. However, the rate of OPLL progression in the thoracic spine was significantly higher than that in the cervical spine regarding thickness (1.4 ± 1.9 vs. 0.6 ± 0.7 mm/year) and CSA (27.7 ± 72.0 vs. 7.3 ± 10.3 mm /year).
CONCLUSION
This is the first study to investigate ligament ossification progression in patients with thoracic myelopathy. The difference between the rate of OPLL and OLF progression in thickness and CSA was not significant. However, the rate of thoracic OPLL progression in thickness and CSA was significantly higher than that in the cervical spine.
Topics: Adult; Aged; Cervical Vertebrae; Female; Humans; Ligamentum Flavum; Male; Middle Aged; Ossification of Posterior Longitudinal Ligament; Ossification, Heterotopic; Osteogenesis; Retrospective Studies; Spinal Cord Diseases
PubMed: 35837729
DOI: 10.1111/os.13291 -
Histology and Histopathology Oct 2014Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This... (Review)
Review
Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This process is induced by inflammation associated with traumatic injury. In an extremely rare genetic disorder called fibrodysplasia ossificans progessiva (FOP), a combination of inflammation associated with minor soft tissue injuries and a hereditary genetic mutation causes massive HO that progressively worsens throughout the patients' lifetime leading to the formation of an ectopic skeleton. An activating mutation in the BMP type I receptor ALK2 has been shown to contribute to the heterotopic lesions in FOP patients, yet recent studies have shown that other events are required to stimulate HO including activation of sensory neurons, mast cell degranulation, lymphocyte infiltration, skeletal myocyte cell death, and endothelial-mesenchymal transition (EndMT). In this review, we discuss the recent evidence and mechanistic data that describe the cellular and molecular mechanisms that give rise to heterotopic bone.
Topics: Animals; Humans; Ossification, Heterotopic
PubMed: 24796520
DOI: 10.14670/HH-29.1281 -
In Vivo (Athens, Greece) 2022Evidence on prophylactic radiotherapy (RT) in hip heterotopic ossification (HO) is sparse and conflicting. The aim of this literature review was to collect and summarize... (Review)
Review
Evidence on prophylactic radiotherapy (RT) in hip heterotopic ossification (HO) is sparse and conflicting. The aim of this literature review was to collect and summarize the available data on RT efficacy in preventing hip HO. The results of this review show that RT is effective in the prevention of hip HO, albeit with large variability across series. Effective prophylactic RT requires optimal treatment fields and time intervals with surgery. On the contrary, there is no clear evidence on the optimal timing (post-operative versus pre-operative RT). Comparisons between prophylactic RT and use of non-steroidal anti-inflammatory drugs showed conflicting results, although most were in favor of RT. In conclusion, RT is an established prophylactic treatment for hip HO. However, optimal dose, technique and timing remain unclear, as does the usefulness of combining RT with drugs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Ossification, Heterotopic; Postoperative Period; Radiotherapy; Radiotherapy Dosage
PubMed: 35241504
DOI: 10.21873/invivo.12735 -
Bone Research Feb 2024Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury....
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. Brain-derived extracellular vesicles (BEVs) are released after traumatic brain injury. These BEVs contain pathogens and participate in interorgan communication to initiate secondary injury in distal tissues. After achillotenotomy, the phagocytosis of BEVs by fibroblasts induces pyroptosis, which is a highly inflammatory form of lytic programmed cell death, in the injured tendon. Fibroblast pyroptosis leads to an increase in calcium and phosphorus concentrations and creates a microenvironment that promotes osteogenesis. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk suppressed fibroblast pyroptosis and effectively prevented the onset of heterotopic ossification after neuronal injury. The use of a pyroptosis inhibitor represents a potential strategy for the treatment of neurogenic heterotopic ossification.
Topics: Humans; Rats; Animals; Brain; Ossification, Heterotopic; Brain Injuries, Traumatic; Blood-Brain Barrier; Extracellular Vesicles
PubMed: 38383487
DOI: 10.1038/s41413-023-00310-8 -
Orthopadie (Heidelberg, Germany) Nov 2023Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the... (Review)
Review
BACKGROUND
Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible.
AIM OF THE RECOMMENDATIONS
This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.
Topics: Humans; Myositis Ossificans; Mutation; Ossification, Heterotopic; Bone Morphogenetic Proteins; Delivery of Health Care
PubMed: 37603129
DOI: 10.1007/s00132-023-04425-y -
Journal of the American Veterinary... May 2016
Topics: Animals; Female; Horse Diseases; Horses; Nasal Polyps; Ossification, Heterotopic
PubMed: 27135668
DOI: 10.2460/javma.248.10.1131 -
Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva.British Journal of Clinical Pharmacology Jun 2019Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and significant disability. FOP is progressive and many patients are wheelchair-bound by the 3rd decade of life. FOP is caused by an activating mutation in the ACVR1 gene, which encodes the activin A Type 1 receptor. Aberrant signalling through this receptor leads to abnormal activation of the pSMAD 1/5/8 pathway and triggers the formation of bone outside of the skeleton. There is no curative therapy for FOP; however, exciting advances in novel therapies have developed recently. Here, we review the clinical and translational pharmacology of three drugs that are currently in clinical trials (palovarotene, REGN 2477 and rapamycin) as well as other emerging treatment strategies for FOP.
Topics: Animals; Bone Remodeling; Bone and Bones; Humans; Myositis Ossificans; Ossification, Heterotopic; Pyrazoles; Signal Transduction; Sirolimus; Stilbenes; Treatment Outcome
PubMed: 30501012
DOI: 10.1111/bcp.13823