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Heterotopic ossification (HO) refers to abnormal bone formation in soft tissues, which is a common complication of traumatic spinal cord injury (SCI). Current therapeutic approaches are non-specific, have limited efficacy and pose serious off-target effects due to insufficient knowledge of HO mechanisms. In the absence of clinically relevant models of traumatic SCI-associated HO, a novel mouse model of polytrauma with concomitant SCI and musculotendinous injury (MTI) was developed. SCI was induced by T9-T10 spinal cord transection, and muscle crush/tenotomy was performed on left quadricepses (SCI+MTI), leaving right limbs intact as internal controls. Age and sex-matched control mice underwent left hindlimb MTI alone or SCI with left quadriceps crush only (SCI+MI). High-resolution micro-computed tomography revealed variable amounts of ectopic mineral deposits only in injured hindlimbs of SCI+MI and SCI+MTI mice. Median ectopic mineral volumes in SCI+MTI mice were higher than SCI+MI mice at 1 and 4 weeks postoperative. Histology of serial sections confirmed von Kossa-positive mineral colocalizing with ALP-positive osteoblast activity and TRAP-positive osteoclast activity, with a significant increase in ALP between both timepoints. Immunofluorescence indicated F4/80-positive macrophages infiltrating ectopic mineral in SCI+MTI mice at 1 week postoperative, and Osterix-positive osteoblasts lining trabecular bone in HO at 4 weeks postoperative. Orthotopic bone loss manifested as cortical thinning and trabecular bone loss in femurs of SCI mice at 4 weeks postoperative. This study thus identifies SCI+MTI mice as a clinically relevant small animal model of polytrauma with SCI in which to study pathogenic mechanisms and assess novel therapeutic approaches to SCI-associated HO.

Osseous metaplasia is considered as a response to insults such as chronic inflammation or mucin extravasation in colorectal polyps. we report two cases of osseous metaplasia in juvenile (retention) polyps as incidental histopathological findings in a case of rectal juvenile polyposis and a patient with solitary rectal juvenile polyp. Osseous metaplasia can occur in colorectal juvenile polyps and is considered a probable response to mucin extravasation and/or chronic inflammation. The clinical and prognostic significance of osseous metaplasia in these polyps is unknown. [ABSTRACT FROM AUTHOR]

Ossa cordis, bones located within the heart trigones, are often classified as heterotopic or ectopic bones. Despite their high prevalence in cattle and some other bovids, little is known about their structure or development. Scanning electron microscopy, X-ray microtomography, gross dissections, and measurements showed the anatomical locations, prevalence, shapes, and measurements of the cardiac bones in both Egyptian Baladi cattle and Holstein-Friesians. All cattle (n = 12) had an Ossa cordis dextrum (average = 50.70 × 20.91 × 5.40 mm). Additionally, 80% Egyptian Baladi and 57% Holstein-Friesian had a smaller Ossa cordis sinistrum (average = 24.94 × 12.75 × 4.12 mm). Egyptian Baladi Ossa cordis were smaller than observed in Holstein-Friesians. Energy-dispersive X-ray analysis showed the elemental constitution (carbon, oxygen, calcium, nitrogen, phosphorus, sodium, and magnesium) of Ossa cordis and Cartilago cordis. These imaging techniques, plus four histological stains (hematoxylin and eosin, Crossman's trichrome, Alcian blue with Van Gieson, and Sirius Red) and microscopy, demonstrated osteoblasts, osteocytes, osteoclasts, astrocytes, blood vessels, bone marrow, lamellar and woven bone, cortical bone, trabeculations with pores and canaliculi, and fibrous components including collagen in the Ossa cordis dextrum and sinistrum. Hyaline cartilage and fibrocartilage (chondrocytes and cartilage matrix) were found within and surrounding the Ossa cordis. These findings were additionally compared against other cattle breeds and species., Competing Interests: Conflict of Interest The authors declare that they have no competing interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America.)

Bone defects are a major threat to human health, and heterotopic bone provides advantages that other materials do not provide in the treatment of bone defects. MPEG-PCL microspheres loaded with bone morphogenetic protein-2 (BMP-2/MPEG-PCL-MS) are an emerging means of culturing heterotopic bone. However, the effect of such microspheres on the quality of heterotopic bone osteogenesis has rarely been studied. The performance of heterotopic bone as a bone repair material has also rarely been reported. To explore the effect of microspheres on heterotopic bone osteogenesis and to explore the performance of heterotopic bone in bone repair, we designed compression tests, nanoindentation tests, and a finite element (FE) simulation. The effects of microspheres on the quality of heterotopic bone osteogenesis and performance of heterotopic bone as a bone repair material were evaluated from the mechanical properties, material properties, and FE simulation. The results demonstrate that eight-week heterotopic bone using microspheres has suitable mechanical and material properties, performs well in bone repair FE simulation, and can meet the material requirements of bone repair. Hence, this heterotopic bone as bone repair material has promising potential for clinical applications, and provides a good strategy for combination between tissue engineering and pharmaceutical science.

This case study documents an unusual heterotopic ossification with associated pseudarthroses of the lumbar spine. We examined the partial skeletal remains of an adult from a Late Bronze Age (Mycenaean Late Helladic IIB‐IIIA1 period, approximately1400–1375 BCE) chamber tomb from the Athenian Agora excavations in Greece. This individual had a large bony mass in the region of the intertransversarius muscle that spanned L3–L5 vertebrae and formed pseudarthroses at the superior and inferior ends. The differential diagnosis of the bony mass included dystrophic and neoplastic calcifications and myositis ossificans traumatica (MOT). MOT is a benign heterotopic bone growth typically found in skeletal muscles. MOT usually results from a trauma and is most commonly found in the thigh, buttocks, or upper arm, although it has been documented clinically in other areas as well, such as in paravertebral muscles. The mature, remodelled cortex of the bony mass and the two well‐developed pseudarthroses indicate that this individual lived with this condition for a number of years. [ABSTRACT FROM AUTHOR]

Introduction. Nonhereditary heterotopic ossification (NHO) is a common complication of trauma. Progressive osseous heteroplasia (POH) and fibrodysplasia ossificans progressiva (FOP) are rare genetic causes of heterotopic bone. In this article, we detail the vascular patterning associated with genetic versus NHO. Methods. Vascular histomorphometric analysis was performed on patient samples from POH, FOP, and NHO. Endpoints for analysis included blood vessel (BV) number, area, density, size, and wall thickness. Results. Results demonstrated conserved temporal dynamic changes in vascularity across all heterotopic ossification lesions. Immature areas had the highest BV number, while the more mature foci had the highest BV area. Most vascular parameters were significantly increased in genetic as compared with NHO. Discussion. In sum, both genetic and NHO show temporospatial variation in vascularity. These findings suggest that angiogenic pathways are potential therapeutic targets in both genetic and nonhereditary forms of heterotopic ossification. [ABSTRACT FROM AUTHOR]

Abstract A 3-year-old male guinea pig (Cavia porcellus) presented to the UNAM Exotic Pet and Wildlife Teaching Hospital. Clinical signs included hyphema, buphthalmos, goniosynechiae, anterior uveitis, and hypopyon of the ventral iridocorneal angle of the right eye. The right globe was enucleated and submitted for histopathology and the histopathologic findings were consistent with osteosarcoma. Thoracic radiographs did not reveal evidence of other primary tumors or metastasis. Four months later, the patient had pleural friction rub sounds upon auscultation of the lung fields and prescapular lymphadenomegaly. Radiographic evaluation revealed a radiopaque mineral-dense structure in the right caudal pulmonary lobe, suggestive of osteosarcoma metastasis. The presumptive diagnosis was confirmed at necropsy. This is the first report of a primary intraocular osteosarcoma in a guinea pig. [ABSTRACT FROM AUTHOR]

A 7-year-old female spayed domestic shorthair cat was referred to the urology service for nonsurgical urocystolith removal. A urolith was attached to the urothelium by ectopic bone. Interventional removal without surgery was successful. Follow-up evaluation 3 years after urolith removal revealed recurrent uroliths, bladder wall mineralization, and marked renal mineralization. This case illustrates the metaplastic potential of the urothelium and that ectopic bone should be included among the pathological factors that promote lithogenesis. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Severe progressive multifocal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate owing to patient-, disease-, logistical-, and radiation-related issues. The purpose of this study was to develop and validate a scoring system based on plain radiographs for quantitative assessment of HO lesions in patients with FOP.Materials and Methods: Institutional review board approval was obtained from the University of Pennsylvania, and all data comply with Health Insurance Portability and Accountability Act regulations. The University of Pennsylvania Institutional Animal Care and Use Committee approved the use of mice in this study. First, we used a mouse model of FOP-like HO to validate a semiquantitative analog scale for estimating relative heterotopic bone volume. Second, we used this validated scale to estimate the relative amount of HO from a retrospective analysis of plain radiographs from 63 patients with classic FOP. Finally, the scale was applied to a retrospective analysis of computed tomographic images from three patients with FOP.Results: In the FOP-mouse model, the observed rating on the analog scale is highly correlated to heterotopic bone volumes measured by microcomputed tomography (R2 = 0.89). The scoring system that was applied to radiographs of patients with FOP captured the clinical range of HO typically present at all axial and appendicular sites. Analysis of computed tomographic scans of patients with FOP found that observed radiograph ratings were highly correlated with HO volume (R2 = 0.80).Conclusions: The scoring system described here could enable practical, quantitative assessment of HO in clinical trials to evaluate new treatment modalities, especially for FOP. The development of the six-point analog scale described here provides and validates a much-needed, reproducible, and quantifiable method for describing and assessing HO in patients with FOP. This scale has the potential to be a key descriptor that can inform patients with FOP and clinicians about disease progression and response of HO lesions to interventions and treatments. [ABSTRACT FROM AUTHOR]

Abstract Background Trauma, osteomyelitis, bone tumour resections and congenital deformities are the main causes of bone deficiency in which autologous graft is the preferred treatment, but usually the bone supplies are limited. Methods An experimental model of heterotopic bone formation in the subcutaneous abdominal area of dogs was developed. This model consists in omentum wrapped implants constituted by collagen type 1 sponges embedded with demineralized bone powder, calcium cloride, thrombin and platelet rich plasma; the implant is totally converted in trabecular bone after four months of implantation. This model was improved by accelerating bone production, after the isolation of the most conspicuous histological constituents (inflammatory, bone and adipose tissues) by laser microdisection and purified from them RNA that was used to determine by RT‐PCR the gene expression kinetics of the most important growth bone factors. Then, the most abundant and rapidly synthesized factors were produced by genetic engineering in tobacco plants. Results Bone morphogenetic proteins 2 and 7 and transforming growth factor‐β1were the most rapidly and highly synthesized factors, and they were efficiently produced in a genetic engineering plant based system in tobacco leaves. Their incorporation as recombinant proteins in the scaffold collagen sponge induced in just one month mature heterotopic bone. Conclusion This study demonstrates for the first time that this plant system is able to produce recombinant bone growth factors in high amount and at low cost, and they were highly efficient to rapidly induce bone formation in abdominal implants potentially useful for autotransplantation.

ABSTRACT Available evidence indicates that some Tie2-expressing (Tie2+) cells serve as multipotent progenitors that have robust BMP-dependent osteogenic activity and mediate heterotopic ossification (HO). Since signaling through the G protein Gi is required for cell motility, we hypothesized that blockade of endogenous Gi signaling in Tie2+ cell populations would prevent HO formation. Blockade of Gi signaling in Tie2+ cells was accomplished in transgenic mice with expression of pertussis toxin (PTX) under the control of the Tie2 promoter (Tie2+/PTX+). Bone formation within HOs was evaluated 2 weeks after BMP injection. Expression of PTX in Tie2+ cells significantly reduced the bone volume (BV) of HOs in male and female mice. Orthotopic bones were assessed at the distal femur and expression of PTX significantly increased trabecular bone fractional volume and bone formation rate in females only. In adult Tie2+/GFP+ mice, GFP+ cells appeared both inside and at the surfaces of bone tissue within HOs and in orthotopic bones. In summary, blockade of Gi signaling in Tie2+ cells reduced the accrual of HOs and stimulated osteogenesis in orthotopic bones. Targeting of Gi protein coupled receptors in Tie2+ cells may be a novel therapeutic strategy in states of abnormal bone formation such as osteoporosis and HO. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1212-1217, 2015. [ABSTRACT FROM AUTHOR]

Background aims. Decreased bone formation with age is believed to arise, at least in part, because of the influence of the senescent microenvironment. In this context, it is unclear whether multipotent stromal cell (MSC)-based therapies would be effective for the treatment of bone diseases. Methods. With the use of a heterotopic bone formation model, we investigated whether MSC-derived osteogenesis is impaired in aged mice compared with young mice. Results. We found that bone formation derived from MSCs is not reduced in aged mice. These results are supported by the unexpected finding that conditioned media collected from ionizing radiation--induced senescent MSCs can stimulate mineralization and delay osteoclastogenesis in vitro. Conclusions. Overall, our results suggest that impaired bone formation with age is mainly cellautonomous and provide a rationale for the use of MSC-based therapies for the treatment of bone diseases in the elderly. [ABSTRACT FROM AUTHOR]

Two cases with multiple recurrences of temporomandibular joint ankylosis and multiple failed interposition/gap arthroplasty procedures are presented here. Heterotopic bone formation was thought to be the reason. Indomethacin prophylaxis for prevention of heterotopic new bone formation at the osteoarthrectomy site was used as an adjuvant to surgery, in dosages of 75 mg/day for six weeks. Indomethacin is used frequently in hip and elbow arthroplasties to prevent heterotopic ossification, but its use in temporomandibular joint is not routine. The presented cases did not develop further recurrence and attained stable mouth opening over two-year follow-up after osteoarthrectomy and oral indomethacin. [ABSTRACT FROM AUTHOR]

Heterotopic ossification (HO) is a dynamic, complex pathologic process that often occurs after severe polytrauma trauma, resulting in an abnormal mesenchymal stem cell differentiation leading to ectopic bone growth in soft-tissues including tendons, ligaments, and muscles. The abnormal bone structure and location induce pain and loss of mobility. Recently, we observed that NGF (Nerve growth factor)-responsive TrkA (Tropomyosin receptor kinase A)-expressing nerves invade sites of soft-tissue trauma, and this is a necessary feature for heterotopic bone formation at sites of injury. Here, we assayed the effects of the partial TrkA agonist Gambogic amide (GA) in peritendinous heterotopic bone after extremity trauma. Mice underwent HO induction using the burn/tenotomy model with or without systemic treatment with GA, followed by an examination of the injury site via radiographic imaging, histology, and immunohistochemistry. Single-cell RNA Sequencing confirmed an increase in neurotrophin signaling activity after HO-inducing extremity trauma. Next, TrkA agonism led to injury site hyper-innervation, more brisk expression of cartilage antigens within the injured tendon, and a shift from FGF to TGFβ signaling activity among injury site cells. Nine weeks after injury, this culminated in higher overall levels of heterotopic bone among GA-treated animals. In summary, these studies further link injury site hyper-innervation with increased vascular ingrowth and ultimately heterotopic bone after trauma. In the future, modulation of TrkA signaling may represent a potent means to prevent the trauma-induced heterotopic bone formation and improve tissue regeneration., (© The Author(s) 2022. Published by Oxford University Press.)