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Biomolecules Mar 2024Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. (Review)
Review
BACKGROUND
Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized.
PURPOSE OF REVIEW
This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP.
FUTURE PERSPECTIVES
The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Cell Differentiation; Signal Transduction; Inflammation
PubMed: 38540775
DOI: 10.3390/biom14030357 -
Biomolecules Mar 2024Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as... (Review)
Review
Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both.
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Osteogenesis; Bone and Bones
PubMed: 38540768
DOI: 10.3390/biom14030349 -
Biomolecules Mar 2024Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the...
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the molecular mechanisms underlying the ectopic bone formation and expansion in FOP is critical for the effective treatment or prevention of HO. Here we find that Hh signaling activation is required for the aberrant ectopic bone formation in FOP. We show that the expression of (), a Hh ligand, as well as downstream Hh signaling, was increased in ectopic bone lesions in ; mice. Pharmacological treatment with an Ihh-neutralizing monoclonal antibody dramatically reduced chondrogenesis and ectopic bone formation. Moreover, we find that the activation of Yap in the FOP mouse model and the genetic deletion of halted ectopic bone formation and decreased expression. Our mechanistic studies showed that Yap and Smad1 directly bind to the Ihh promoter and coordinate to induce chondrogenesis by promoting expression. Therefore, the Yap activation in FOP lesions promoted ectopic bone formation and expansion in both cell-autonomous and non-cell-autonomous manners. These results uncovered the crucial role of the Yap-Ihh axis in FOP pathogenesis, suggesting the inhibition of Ihh or Yap as a potential therapeutic strategy to prevent and reduce HO.
Topics: Mice; Animals; Hedgehog Proteins; Chondrogenesis; Osteogenesis; Ossification, Heterotopic; Myositis Ossificans; Mutation
PubMed: 38540766
DOI: 10.3390/biom14030347 -
Osteoarthritis and Cartilage Mar 2024Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis...
OBJECTIVE
Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis (PTOA). Based on lipolytic and immunoregulatory actions of norepinephrine, we hypothesized that intra-articular β-adrenergic receptor (βAR) stimulation would suppress PTOA-associated inflammation in the infrapatellar fat pad (IFP) and synovium.
DESIGN
We used the βAR agonist isoproterenol to perturb intra-articular metabolism 3.5 weeks after applying a non-invasive single-load compression injury to knees of 12-week-old male and female mice. We examined the acute effects of intra-articular isoproterenol treatment relative to saline on IFP histology, multiplex gene expression of synovium-IFP tissue, synovial fluid metabolomics, and mechanical allodynia.
RESULTS
Injured knees developed PTOA pathology characterized by heterotopic ossification, articular cartilage loss, and IFP atrophy and fibrosis. Isoproterenol suppressed the upregulation of pro-fibrotic genes and downregulated the expression of adipose genes and pro-inflammatory genes (Adam17, Cd14, Icam1, Csf1r, and Casp1) in injured joints of female (but not male) mice. Analysis of published single-cell RNA-seq data identified elevated catecholamine-associated gene expression in resident-like synovial-IFP macrophages after injury. Injury substantially altered synovial fluid metabolites by increasing amino acids, peptides, sphingolipids, phospholipids, bile acids, and dicarboxylic acids, but these changes were not appreciably altered by isoproterenol. Intra-articular injection of either isoproterenol or saline increased mechanical allodynia in female mice, whereas neither substance affected male mice.
CONCLUSIONS
Acute βAR activation altered synovial-IFP transcription in a sex and injury-dependent manner, suggesting that women with PTOA may be more sensitive than men to treatments targeting sympathetic neural signaling pathways.
PubMed: 38527663
DOI: 10.1016/j.joca.2024.03.109 -
International Journal of Surgery Case... Apr 2024Fibrodysplasia Ossificans Progressiva is an ultra-rare genetic disorder of progressive soft tissue ossification. Due to unawareness and poor clinical suspicion, the rate...
INTRODUCTION AND IMPORTANCE
Fibrodysplasia Ossificans Progressiva is an ultra-rare genetic disorder of progressive soft tissue ossification. Due to unawareness and poor clinical suspicion, the rate of misdiagnosis, delay in diagnosis, and unnecessary diagnostic procedures leading to permanent injury and lifelong disability is common. Here we report this rare genetic disorder in a six years old child who was initially misdiagnosed as multiple exostoses and operated on.
CASE PRESENTATION
A 6 year old child presented with swellings over the posterior neck and back for four years. The patient was misdiagnosed as a case of multiple exostoses and an excisional biopsy was done a year back. The swelling worsened after the excision; currently, she cannot move her neck from side to side, and flex and extend. Examination revealed multiple hard and slightly tender masses over the posterior neck, para scapular and thoracolumbar para spinal region. She also has hallux valgus deformity that had been present since birth. CT (computed tomography) scan confirmed extensive extra-skeletal soft tissue ossification.
CLINICAL DISCUSSION
The progression of heterotopic ossification is characteristically anatomic and orderly, typically initially involving the body's dorsal, axial, cranial, and proximal regions and later in the ventral, appendicular, caudal, and distal regions. Skeletal muscles of the tongue, diaphragm, extra-ocular muscles, cardiac muscles, and smooth muscles are inexplicably spared.
CONCLUSION
Early diagnosis prevents potentially harmful diagnostic and therapeutic procedures. The characteristic big toes malformation is the most important and best key for the early suspicion of the diagnosis.
PubMed: 38513414
DOI: 10.1016/j.ijscr.2024.109548 -
Stem Cell Research & Therapy Mar 2024Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I...
BACKGROUND
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP.
METHODS
In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSC), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSC on BMP signaling pathways and HO development, respectively.
RESULTS
We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs.
CONCLUSIONS
These results offer a new perspective for treating FOP through stem cell therapy.
Topics: Female; Humans; Mice; Animals; Myositis Ossificans; Ossification, Heterotopic; Bone Morphogenetic Proteins; Signal Transduction; Mice, Transgenic; Mutation; Activin Receptors, Type II
PubMed: 38500216
DOI: 10.1186/s13287-024-03691-7 -
Tissue & Cell Jun 2024Nano-hydroxyapatite (nHA)/ gel porous scaffolds loaded with WSM carriers are promising bone replacement materials that can improve osseointegration ability. This...
BACKGROUND/PURPOSE
Nano-hydroxyapatite (nHA)/ gel porous scaffolds loaded with WSM carriers are promising bone replacement materials that can improve osseointegration ability. This investigation aimed to evaluate the osteoinductive activity by implanting the composition of nano-hydroxyapatite (nHA)/ Gel porous scaffolds as a carrier of WSM via an animal model.
MATERIALS AND METHODS
WSM was extracted and nHA was added to the matrix to construct porous composite scaffolds. The dose-effect curve of WSM concentration and alkaline phosphatase (ALP) activity was made by culturing rat osteoblasts and examining the absorbance. Three different materials were implanted into critical size defects (CSD) in the skulls of rats, which were further divided into four groups: WSM nHA /Gel group, n-WSM nHA /Gel group, HA powder group, and control group.
RESULTS
WSM (150 μg/mL-250μg/mL) effectively improved the activity of ALP in rat osteoblasts. All rats in each group had normal healing. WSM-loaded nHA /Gel group showed better performance on newly-formed bone tissue of rat skull and back at 4th week and 8th week, respectively. At the 4th week, the network of woven bone formed in the WSM-loaded nHA/Gel scaffold material. At 8th week, the reticular trabecular bone in the WSM-loaded scaffold material became dense lamellar bone, and the defect was mature lamellar bone. In the subcutaneous implantation experiment, WSM-loaded nHA/Gel scaffold material showed a better performance of heterotopic ossification than the pure nHA/Gel scaffold material.
CONCLUSION
WSM promotes osteoblast differentiation and bone mineralization. The results confirm that the nHA/ Gel Porous Scaffold with Nacre Water-Soluble Matrix has a significant bone promoting effect and can be used as a choice for tissue engineering to repair bone defects.
Topics: Animals; Tissue Scaffolds; Osteogenesis; Durapatite; Rats; Osteoblasts; Porosity; Male; Alkaline Phosphatase; Gels; Rats, Sprague-Dawley; Water; Skull
PubMed: 38489914
DOI: 10.1016/j.tice.2024.102347 -
Bone Research Mar 2024While hypoxic signaling has been shown to play a role in many cellular processes, its role in metabolism-linked extracellular matrix (ECM) organization and downstream...
While hypoxic signaling has been shown to play a role in many cellular processes, its role in metabolism-linked extracellular matrix (ECM) organization and downstream processes of cell fate after musculoskeletal injury remains to be determined. Heterotopic ossification (HO) is a debilitating condition where abnormal bone formation occurs within extra-skeletal tissues. Hypoxia and hypoxia-inducible factor 1α (HIF-1α) activation have been shown to promote HO. However, the underlying molecular mechanisms by which the HIF-1α pathway in mesenchymal progenitor cells (MPCs) contributes to pathologic bone formation remain to be elucidated. Here, we used a proven mouse injury-induced HO model to investigate the role of HIF-1α on aberrant cell fate. Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analyses of the HO site, we found that collagen ECM organization is the most highly up-regulated biological process in MPCs. Zeugopod mesenchymal cell-specific deletion of Hif1α (Hoxa11-CreER; Hif1a) significantly mitigated HO in vivo. ScRNA-seq analysis of these Hoxa11-CreER; Hif1a mice identified the PLOD2/LOX pathway for collagen cross-linking as downstream of the HIF-1α regulation of HO. Importantly, our scRNA-seq data and mechanistic studies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1α deletion. From a translational aspect, a pan-LOX inhibitor significantly decreased HO. A newly screened compound revealed that the inhibition of PLOD2 activity in MPCs significantly decreased osteogenic differentiation and glycolytic metabolism. This suggests that the HIF-1α/PLOD2/LOX axis linked to metabolism regulates HO-forming MPC fate. These results suggest that the HIF-1α/PLOD2/LOX pathway represents a promising strategy to mitigate HO formation.
Topics: Animals; Mice; Collagen; Disease Models, Animal; Extracellular Matrix; Hypoxia; Ossification, Heterotopic; Osteogenesis; Transcription Factors
PubMed: 38472175
DOI: 10.1038/s41413-024-00320-0 -
Scientific Reports Mar 2024The presence of heterotopic ossification (HO) after primary total knee replacement (TKR) is rare and associated with limited mobility and stiffness of the knee. This...
The presence of heterotopic ossification (HO) after primary total knee replacement (TKR) is rare and associated with limited mobility and stiffness of the knee. This study aimed to identify if the arthroscopic debridement after TKR could decrease HO and improve the function and range of motion. Thirty HO patients after TKR were retrospectively separated into 2 cohorts. 15 patients of group A accepted the arthroscopic debridement, while 15 patients of group B only had non-operative treatment, mainly including oral nonsteroidal anti-inflammatory drugs (NSAIDs) and rehabilitative treatment. Visual analog scale (VAS) scores, knee society knee scores (KSS), range of motion (knee flexion and knee extension) were obtained before treatment and at 1 month, 3 months, and 6 months after treatment. Radiography of after-treatment was also evaluated to assess the changes in HO. There were 3 males and 27 females with a mean age of 67.4 ± 0.8 years in group A and 68.2 ± 1.3 in group B. The onset time of HO was 3-6 months. The maximum size of the ossification was < 2 cm in 23 knees, 2 cm < heterotopic bone < 5 cm in 6 knees and > 5 cm in 1 knee. The size of HO decreased gradually in all knees by X-ray film at the last follow-up. There were no significant differences in VAS scores after replacement between two groups (p > 0.05). The average range of motion preoperatively in group A was - 15.2-90.6°, which postoperatively increased to - 4.2-110.0°. Meanwhile, the KSS scores and average range of motion of the group A were better than those of the group B at each follow-up time after treatment. Arthroscopic debridement can decrease HO seen from postoperative X-rays, improve the function and range of motion, as well as the pain remission between two groups are comparable. Consequently, arthroscopic resection of HO after TKR is recommended as soon as there is aggravating joint stiffness.
Topics: Male; Female; Humans; Aged; Arthroplasty, Replacement, Knee; Retrospective Studies; Debridement; Treatment Outcome; Knee Joint; Ossification, Heterotopic; Range of Motion, Articular
PubMed: 38467720
DOI: 10.1038/s41598-024-56300-1 -
International Journal of Surgery Case... Apr 2024Heterotopic ossification is forming a new bone in tissues that do not normally ossify. HO was first reported in 1901 by Askanazy and Lubarsh in a case report study. The...
INTRODUCTION AND IMPORTANCE
Heterotopic ossification is forming a new bone in tissues that do not normally ossify. HO was first reported in 1901 by Askanazy and Lubarsh in a case report study. The range of HO is wide from minute foci to large clinically significant ossification. The incidence of HO in abdominal scars is extremely low.
CASE PRESENTATION
We present an 84-year-old man referred to our hospital after an unsuccessful elective colostomy reversal in a local hospital. The colostomy was made for fecal diversion after sigmoidectomy due to treatment of sigmoid volvulus about three months ago. The patient had a past medical history of hypertension for 8 years under treatment of amiloride.
CLINICAL DISCUSSION
In general appearance, the patient was not ill or toxic. Vital signs were normal. Postoperatively Patient did not defecate. In his physical examination was not found abdominal tenderness or rebound tenderness. The patient underwent laparotomy which revealed significant retroperitoneal adhesion and colostomy was reversed. Accidentally was found a dense structure with bone-like consistency in the abdominal wall close to the scar was resected. The specimen Pathologic examination showed metaplastic bone deposition with mature bone trabeculae and heterotopic ossification was confirmed.
CONCLUSION
We report a rare case of HO that was identified at the abdominal wall. Heterotopic ossification can lead to serious complications. However, in symptomatic patients, surgical excision is an acceptable treatment, unlike in asymptomatic patients.
PubMed: 38460290
DOI: 10.1016/j.ijscr.2024.109469