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JCI Insight Jul 2022Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the... (Review)
Review
Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.
Topics: Bone and Bones; Humans; Myositis Ossificans; Ossification, Heterotopic
PubMed: 35866484
DOI: 10.1172/jci.insight.158996 -
The Journal of Bone and Joint Surgery.... Jul 2015➤ Heterotopic ossification occurs most commonly after joint arthroplasty, spinal cord injury, traumatic brain injury, blast trauma, elbow and acetabular fractures, and... (Review)
Review
➤ Heterotopic ossification occurs most commonly after joint arthroplasty, spinal cord injury, traumatic brain injury, blast trauma, elbow and acetabular fractures, and thermal injury.➤ The conversion of progenitor cells to osteogenic precursor cells as a result of cell-mediated interactions with the local tissue environment is affected by oxygen tension, pH, availability of micronutrients, and mechanical stimuli, and leads to heterotopic ossification.➤ Radiation and certain nonsteroidal anti-inflammatory medications are important methods of prophylaxis against heterotopic ossification.➤ Well-planned surgical excision can improve patient outcomes regardless of the joint involved or the initial cause of injury.➤ Future therapeutic strategies are focused on targeted inhibition of local factors and signaling pathways that catalyze ectopic bone formation.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthroplasty; Bone Density Conservation Agents; Humans; Ossification, Heterotopic; Risk Factors; Wounds and Injuries
PubMed: 26135077
DOI: 10.2106/JBJS.N.01056 -
Orthopaedic Surgery Aug 2014Today, total knee arthroplasty (TKA) is one the most commonly performed surgeries worldwide. The purpose of this article is to review the appearance of normal post-TKA... (Review)
Review
Today, total knee arthroplasty (TKA) is one the most commonly performed surgeries worldwide. The purpose of this article is to review the appearance of normal post-TKA roentgenographs and describe the correct sequence for their interpretation. It is unwise to depend solely on patients' symptoms when diagnosing TKA complications because serial radiographs can foresee failures well before they manifest clinically. Ideal post-TKA radiographs comprise whole lower extremity anteroposterior and lateral views taken under weight bearing conditions along with a skyline view of the patellofemoral joint. Among other things, weight bearing exposes the true alignment, ligamentous laxity and polyethylene wear. On the basis of follow-up of our TKA cases, we have drawn up a protocol for assessing postoperative X-ray films after TKAs. Following the proposed sequence, surgeon can easily decide how to proceed with follow-up and foresee complications. Careful interpretation of postoperative radiographs after TKA is essential to careful monitoring of patients and implant survival.
Topics: Arthroplasty, Replacement, Knee; Humans; Knee Joint; Knee Prosthesis; Ossification, Heterotopic; Patella; Periprosthetic Fractures; Postoperative Care; Prosthesis Design; Prosthesis Failure; Radiography
PubMed: 25179351
DOI: 10.1111/os.12123 -
BioMed Research International 2019This review is intended to summarize the risk factors, classification, diagnosis, and treatment of heterotopic ossification (HO) of previously published studies. (Review)
Review
BACKGROUND
This review is intended to summarize the risk factors, classification, diagnosis, and treatment of heterotopic ossification (HO) of previously published studies.
RESULTS
Heterotopic ossification is a common complication of total hip arthroplasty. Its prevalence is not the same in all of the patient groups. Frequency of HO varies from 15 to 90%. Hip ankylosis, male gender, and previous history of HO are said to be risk factors with a significant level. Diagnosis is based on a single AP radiograph: the Brooker classification that divides HO into four grades is the most commonly used. The confirmation test that can be used is a bone scan. A great amount of bone metabolic turnover markers have been tested, but none of them seems to be relevant in case of prevention or diagnosis of HO. The most effective prophylactic treatment is radiotherapy or administration of nonsteroidal anti-inflammatory drugs. Over the years a lot of different RT protocols have been tested. Nowadays the most often used regimen is 7 Gy given postoperatively in a single dose. The most commonly prescribed drug in prophylaxis of HO is indomethacin. Also, the efficacy of ibuprofen and diclofenac was proven. Recently researchers focused on selective COX-2 inhibitors. They appear to be as effective as nonselective NSAIDs having less side effects. The one and only treatment of HO is a revision arthroplasty.
Topics: Arthroplasty, Replacement, Hip; Female; Humans; Male; Ossification, Heterotopic; Postoperative Complications; Postoperative Period; Radiography; Risk Factors; Sex Characteristics; Treatment Outcome
PubMed: 31119167
DOI: 10.1155/2019/3860142 -
The Journal of Clinical Investigation Dec 2020Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin...
Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk+Scx+ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cathepsin K; Gene Expression Regulation, Enzymologic; Hedgehog Proteins; Mice; Mice, Transgenic; Ossification, Heterotopic; Repressor Proteins; Signal Transduction; Stem Cells; Tendons
PubMed: 32853181
DOI: 10.1172/JCI132518 -
Internal Medicine (Tokyo, Japan) Aug 2022
Topics: Humans; Ossification, Heterotopic; Temporal Bone
PubMed: 35110494
DOI: 10.2169/internalmedicine.9017-21 -
Neurology India 2022
Topics: Humans; Ossification, Heterotopic; Temporal Bone
PubMed: 35263880
DOI: 10.4103/0028-3886.338720 -
Journal of Bone and Mineral Research :... Oct 2022Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups,... (Randomized Controlled Trial)
Randomized Controlled Trial
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1-2/3-6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1-2/3-6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7-53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 10 mm with palovarotene 10/5 mg; 1.3 × 10 mm with palovarotene 5/2.5 mg; 18.0 × 10 mm with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Pyrazoles; Stilbenes
PubMed: 35854638
DOI: 10.1002/jbmr.4655 -
Journal of Cellular and Molecular... May 2020Much of the similarities of the tissue characteristics, pathologies and mechanisms of heterotopic ossification (HO) formation are shared between HO of tendon and... (Review)
Review
Much of the similarities of the tissue characteristics, pathologies and mechanisms of heterotopic ossification (HO) formation are shared between HO of tendon and ligament (HOTL). Unmet need and no effective treatment has been developed for HOTL, primarily attributable to poor understanding of cellular and molecular mechanisms. HOTL forms via endochondral ossification, a common process of most kinds of HO. HOTL is a dynamic pathologic process that includes trauma/injury, inflammation, mesenchymal stromal cell (MSC) recruitment, chondrogenic differentiation and, finally, ossification. A variety of signal pathways involve HOTL with multiple roles in different stages of HO formation, and here in this review, we summarize the progress and provide an up-to-date understanding of HOTL.
Topics: Biomarkers; Disease Susceptibility; Ligaments; Mesenchymal Stem Cells; Ossification, Heterotopic; Signal Transduction; Tendons
PubMed: 32293797
DOI: 10.1111/jcmm.15240 -
Advanced Science (Weinheim,... Jul 2023Heterotopic ossification (HO) represents an unwanted ossific wound healing response to the soft tissue injury which caused catastrophic limb dysfunction. Recent studies...
Heterotopic ossification (HO) represents an unwanted ossific wound healing response to the soft tissue injury which caused catastrophic limb dysfunction. Recent studies established the involvement of inflammation and cellular senescence in the tissue healing process, though their role in HO still remained to be clarified. Here, a novel crosstalk where the pyroptotic macrophages aroused tendon-derived stem cells (TDSCs) senescence is revealed to encourage osteogenic healing during trauma-induced HO formation. Macrophage pyroptosis blockade reduces the senescent cell burden and HO formation in NLRP3 knockout mice. Pyroptosis-driven IL-1β and extracellular vesicles (EVs) secretion from macrophages are determined to motivate TDSCs senescence and resultant osteogenesis. Mechanistically, pyroptosis in macrophages enhances the exosomal release of high mobility group protein 1 (HMGB1), which directly bounds TLR9 in TDSCs to trigger morbid signaling. NF-κB signaling is confirmed to be the converging downstream pathway of TDSCs in response to HMGB1-containing EVs and IL-1β. This study adds insights into aberrant regeneration-based theory for HO formation and boosts therapeutic strategy development.
Topics: Animals; Mice; Cellular Senescence; HMGB1 Protein; Macrophages; NLR Family, Pyrin Domain-Containing 3 Protein; Ossification, Heterotopic; Wound Healing
PubMed: 37204068
DOI: 10.1002/advs.202207383