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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 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 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 -
The American Journal of the Medical... Dec 2023
Topics: Humans; Temporal Bone; Ossification, Heterotopic
PubMed: 37402435
DOI: 10.1016/j.amjms.2023.06.018 -
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 Clinical Rheumatology :... Oct 2020
Topics: Humans; Ossification, Heterotopic
PubMed: 31261309
DOI: 10.1097/RHU.0000000000001096 -
Current Opinion in Otolaryngology &... Aug 2023Eagle syndrome is a challenging clinical presentation with important potential complications. It can be misdiagnosed due to lack of awareness; this review provides... (Review)
Review
PURPOSE OF REVIEW
Eagle syndrome is a challenging clinical presentation with important potential complications. It can be misdiagnosed due to lack of awareness; this review provides information in terms of diagnosis and management of eagle syndrome.
RECENT FINDINGS
The importance of early diagnosis of this rare disease is preventing the delay in clinical-surgical treatment. As there is not a universally accepted cut-off for styloid process length, the diagnosis should be confirmed by length of process greater than one-third of the length of mandibular ramus in addition to other clinical symptoms and signs. There are both surgical and pharmacological treatment options for these patients.
SUMMARY
Eagle syndrome is a rare clinical condition and its diagnosis is made by physical examination and radiography. When it is suspected by physical examination, definitive diagnosis is confirmed by computed tomography scans of the skull, as the gold standard. Location, degree of elongation of styloid process, and severity and reproducibility of symptoms are important factors in deciding the most appropriate approach. Surgery is frequently the treatment of choice in Eagle syndrome patients. With proper diagnosis and treatment, the prognosis is favourable and recurrence is uncommon.
Topics: Humans; Reproducibility of Results; Temporal Bone; Ossification, Heterotopic; Tomography, X-Ray Computed
PubMed: 37387673
DOI: 10.1097/MOO.0000000000000903