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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 -
EFORT Open Reviews Mar 2024The aim of this study was to provide a comprehensive overview of floating hip injury and attempt to provide a management algorithm.
AIM
The aim of this study was to provide a comprehensive overview of floating hip injury and attempt to provide a management algorithm.
METHODS
PubMed was searched using the terms 'Floating hip' or 'acetabular fracture' and 'Ipsilateral femoral fracture' or 'pelvic fracture' and 'Ipsilateral femoral fracture'. One author performed a preliminary review of the abstracts and references of the retrieved articles.
RESULTS
The mean injury severe score reported was higher than 20. Chest and abdominal injuries, as well as fractures at other sites, were the most common associated injuries. Despite the high disability rate, surgery remained the preferred option for managing these injuries. The surgical timing varied from a few hours to several days and was subjected to the principles of damage control orthopedics. Although, in most cases, fixation of femoral fractures took precedence over pelvic or acetabular fractures, there was still a need to consider the impact of damage control orthopedics, associated injuries, and surgeon's considerations and preferences. Posttraumatic arthritis, neurological deficits, heterotopic ossification, femoral head necrosis, femoral nonunion, and limb inequality were common complications of the floating hip injury.
CONCLUSIONS
The severity of such injuries often exceeds that of an isolated injury and often requires specialized multidisciplinary treatment. In the management of these complex cases, the complexity and severity of the injury should be fully assessed, and an appropriate surgical plan should be developed to perform definitive surgery as early as possible, with attention to prevention of complications during the perioperative period.
PubMed: 38457919
DOI: 10.1530/EOR-23-0013 -
Cell Communication and Signaling : CCS Mar 2024Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be... (Review)
Review
Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD-like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.
Topics: Humans; NF-kappa B; Osteonectin; TOR Serine-Threonine Kinases; Inflammation; Ossification, Heterotopic
PubMed: 38439078
DOI: 10.1186/s12964-024-01533-w -
Arthroscopy Techniques Feb 2024Distal biceps ruptures are common injuries that lead to significant decrease in elbow supination strength and pain. This Technical Note describes a single-incision...
Distal biceps ruptures are common injuries that lead to significant decrease in elbow supination strength and pain. This Technical Note describes a single-incision distal biceps tendon repair using 2 knotless suture anchors. This technique is easily reproducible, is efficient, and has the unique benefits of decreasing the risk of heterotopic ossification and damage to neurovascular structure while providing similar outcomes to other described fixation techniques.
PubMed: 38435242
DOI: 10.1016/j.eats.2023.09.016 -
Internal Medicine (Tokyo, Japan) May 2024We present the case of a 61-year-old man who developed coronavirus disease 2019 (COVID-19) and died during treatment for relapsing polychondritis. The patient was...
We present the case of a 61-year-old man who developed coronavirus disease 2019 (COVID-19) and died during treatment for relapsing polychondritis. The patient was intubated and treated with steroid pulse therapy, remdecivir, antibacterial agents, baricitinib, and tocilizumab. However, his respiratory condition worsened, and he died 108 days after disease onset. An autopsy revealed diffuse alveolar damage in the fibrotic phase in all lung lobes, diffuse pulmonary ossification, and cytomegalovirus-infected cells in the middle lobe of the right lung. We herein discuss the clinical features and pathological findings of COVID-19 in immunosuppressed patients.
Topics: Humans; Male; COVID-19; Middle Aged; Autopsy; SARS-CoV-2; Fatal Outcome; Ossification, Heterotopic; Polychondritis, Relapsing; Pneumonia, Viral; Pandemics; Coronavirus Infections; Lung; Betacoronavirus; Immunocompromised Host; Lung Diseases
PubMed: 38432960
DOI: 10.2169/internalmedicine.3096-23 -
Journal of Orthopaedic Surgery (Hong... 2024To report preliminary clinical results and safety of 3D-printed patient-specific titanium radial head (RH) prosthesis in treatment of the irreparable RH fractures.
PURPOSE
To report preliminary clinical results and safety of 3D-printed patient-specific titanium radial head (RH) prosthesis in treatment of the irreparable RH fractures.
MATERIAL AND METHODS
This multi-centric prospective study included 10 patients (6 men and four women, mean age 41 years (range, 25-64 years)). Three cases were classified as Mason type III and 7 cases as type IV. Patients were assessed preoperatively, intraoperatively, and at 1, 6, 12, 24, 36, and 48 weeks postoperatively. Range of motion (ROM), visual analog scale (VAS) score, Disabilities of the Arm, Shoulder and Hand (DASH) score, Mayo Elbow Performance Score (MEPS), radiology imaging, and laboratory blood and urine testing were evaluated.
RESULTS
The prostheses were implanted utilizing cemented stems in 5 patients and cementless stems in 5 patients. Intraoperatively, well congruency of a prosthesis with capitellum and radial notch of ulna was observed in all cases. All patients had improvement of ROM, VAS score, DASH score, and MEPS during the postoperative follow-ups. At the final follow-up, mean elbow extension was 6.5° (range, 0°-30°), flexion 145° (range, 125°-150°), supination 79° (range, 70°-80°), and pronation 73.5° (range, 45°-80°). Mean VAS score was 0.3 (range, 0-3), DASH score was 12.35 (range, 1.7-23.3), and MEPS was 99.5 (range, 95-100). Postoperative radiographs demonstrated heterotopic ossification in 2 cases, periprosthetic radiolucency in 2 cases, and proximal radial neck resorption in 2 cases. No one had the evidence of capitellar erosion, implant failure, malpositioning, overstuffing, or symptomatic stem loosening. There was no significant alteration of laboratory results or adverse events related to the 3D-printed prosthesis implantation.
CONCLUSION
The preliminary results demonstrated that implantation of the 3D-printed patient-specific titanium RH prosthesis is safe and may be a potential treatment option for irreparable RH fracture.
Topics: Male; Humans; Female; Adult; Prospective Studies; Titanium; Prosthesis Implantation; Elbow Joint; Radius Fractures; Elbow Prosthesis; Printing, Three-Dimensional; Treatment Outcome; Range of Motion, Articular; Retrospective Studies
PubMed: 38430070
DOI: 10.1177/10225536241236806