iMSC-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

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 (iMSCACVR2B-Fc), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1R206H, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSCACVR2B-Fc 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.

Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers.

Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that impede progress in the broader field of medical research into ultra-rare conditions.

AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human ACVR1R206H (Acvr1R206H/+) while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1opt) and artificial miRNAs targeting Activin A and its receptor ACVR1R206H ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of Acvr1R206H/+ skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in Acvr1R206H/+ mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP.

Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP. QUESTIONS/PURPOSES: (1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture? METHODS: We retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, median age 22 years, range 5 to 57 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively. Patients were analyzed at a median follow-up of 6 years (range 18 months to 20 years), and none was lost to follow-up. Clinical records for each patient were reviewed by the referring physician-author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at the time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention (2 mg/kg once daily for 4 days), patient-reported flareups (episodic inflammatory lesions of muscle and deep soft connective tissue characterized variably by swelling, escalating pain, stiffness, and immobility) after the fracture, follow-up radiographs of the fracture if available, HO formation (yes or no) as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion at least 6 months after and as long as 20 years after the fracture. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients and were independently reviewed by the referring physician-author and senior author for radiographic criteria of fracture healing and HO. RESULTS: Radiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. Painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. In seven percent (three of 41) of fractures, patients reported increased pain or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flareup. The same three patients reported a residual loss of motion 1 year after the fracture compared with their prefracture status. HO developed in 10% (three of 31) of the fractures for which follow-up radiographs were available. Patient-reported loss of motion occurred in 10% (four of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosis). CONCLUSION: Most fractures treated nonoperatively in individuals with FOP healed with few flareups, little or no HO, and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering nonoperative treatment for fractures in individuals with FOP. Physicians who treat fractures in patients with FOP should consult with a member of the International Clinical Council listed in the FOP Treatment Guidelines ( https://www.iccfop.org ). LEVEL OF EVIDENCE: Level IV, therapeutic study.

Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery.

Heterotopic ossification is the most disabling feature of fibrodysplasia ossificans progressiva, an ultra-rare genetic disorder for which there is currently no prevention or treatment. Most patients with this disease harbor a heterozygous activating mutation (c.617 G > A;p.R206H) in ACVR1. Here, we identify recombinant AAV9 as the most effective serotype for transduction of the major cells-of-origin of heterotopic ossification. We use AAV9 delivery for gene replacement by expression of codon-optimized human ACVR1, ACVR1R206H allele-specific silencing by AAV-compatible artificial miRNA and a combination of gene replacement and silencing. In mouse skeletal cells harboring a conditional knock-in allele of human mutant ACVR1 and in patient-derived induced pluripotent stem cells, AAV gene therapy ablated aberrant Activin A signaling and chondrogenic and osteogenic differentiation. In Acvr1(R206H) knock-in mice treated locally in early adulthood or systemically at birth, trauma-induced endochondral bone formation was markedly reduced, while inflammation and fibroproliferative responses remained largely intact in the injured muscle. Remarkably, spontaneous heterotopic ossification also substantially decreased in in Acvr1(R206H) knock-in mice treated systemically at birth or in early adulthood. Collectively, we develop promising gene therapeutics that can prevent disabling heterotopic ossification in mice, supporting clinical translation to patients with fibrodysplasia ossificans progressiva.

The impact of fibrodysplasia ossificans progressiva (FOP) on patients and their family members: results from an international burden of illness survey.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, genetic disorder of heterotopic ossification within soft, connective tissues resulting in limited joint function and severe disability. We present results from an international burden of illness survey (NCT04665323) assessing physical, quality of life (QoL), and economic impacts of FOP on patients and family members. METHODS: Patient associations in 15 countries invited their members to participate; individuals with FOP and their family members were eligible. The survey was available online, in 11 languages, from 18 January-30 April 2021. Participants responded to assessments measuring joint function, QoL, healthcare service and living adaptation utilization, out-of-pocket costs, employment, and travel. RESULTS: The survey received 463 responses (patients, n = 219; family members, n = 244). For patients, decreased joint function was associated with reduced QoL and greater reliance on living adaptations. Nearly half of primary caregivers experienced a mild to moderate impact on their health/psychological wellbeing. Most primary caregivers and patients (≥18 years) reported that FOP impacted their career decisions. CONCLUSIONS: Data from this survey will improve understanding of the impact of FOP on patients and family members, which is important for identifying unmet needs, optimizing care, and improving support for the FOP community.

Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.

[Progressive myositis ossificans: Case report]. / Miositis osificante progresiva: reporte de un caso.

Background: Myositis ossificans progressiva (MOP) is a low prevalence hereditary connective tissue disease (1:2,000,000 habitants). It is characterized by heterotopic ossification with an uncertain behavior that has been exceptionally related to neoplasms. The objective was to know the coexistence of MOP with neoplasms of mesodermal origin, so that they can be considered in the diagnosis of other patients, as well as formulate hypotheses to clarify their association. Clinical case: 27-year-old female with right gluteal and ischitiobial muscle pain that increased with exercise, without remission with analgesics until limiting the mobility of both extremities. A bone series was requested where areas of heterogeneous radiolucency were evidenced in the region of, both, thighs and pelvis in an irregular manner, similar to bone density, which was compatible with the ultrasound and tomographic findings; we concluded that they were images of myositis ossificans of the hip. The patient reported gastric symptoms and an endoscopy was requested, which histopathologically reported diffuse gastric carcinoma with signet ring cells; cabinet images showed an ovarian tumor. Conclusion: MOP is a low prevalence disease, which is why its knowledge and suspicion are essential for the diagnosis. We found little literature that involves the three entities; therefore, their pathophysiology and understanding is limited. Regarding MOP, at this moment there is no curative treatment; however, an accurate diagnosis allows to start rehabilitation in a timely manner with an improvement in the quality of life.

Introducción: la miositis osificante progresiva (MOP) es una enfermedad hereditaria del tejido conectivo de baja prevalencia (1:2,000,000 habitantes). Se caracteriza por osificación heterotópica con un comportamiento incierto que excepcionalmente se ha relacionado con neoplasias. Se buscó conocer la coexistencia de la MOP con neoplasias de origen mesodérmico, para que sean consideradas en el diagnóstico de otros pacientes, así como formular hipótesis para esclarecer su asociación. Caso clínico: mujer de 27 años con dolor de músculo isquitiobial y glúteo derecho que incrementaba con el ejercicio, sin remisión con analgésicos hasta limitar la movilidad de ambas extremidades. Se solicitó una serie ósea donde se evidenciaron zonas de radiolucidez heterogénea en la región de ambos muslos y pelvis de manera irregular, semejante a densidad ósea, que fue compatible con los hallazgos ecográficos y tomográficos; se concluyó que eran imágenes relacionadas con miositis osificante de cadera. La paciente refirió sintomatología gástrica y se solicitó una endoscopía que histopatológicamente reportó carcinoma gástrico difuso con células en anillo de sello; las imágenes de gabinete mostraron tumoración ovárica. Conclusión: la MOP es una patología de baja prevalencia, por lo que su conocimiento y sospecha son fundamentales para el diagnóstico. Hay poca literatura que involucre a las tres entidades; por ende, su fisiopatología y comprensión es limitada. En cuanto a la MOP, aún no hay un tratamiento curativo; sin embargo, el diagnóstico certero permite iniciar rehabilitación de manera oportuna con mejoría de la calidad de vida.

Allele-Selective LNA Gapmers for the Treatment of Fibrodysplasia Ossificans Progressiva Knock Down the Pathogenic ACVR1R206H Transcript and Inhibit Osteogenic Differentiation.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by episodic heterotopic ossification. The median life span of people with this disorder is ∼40 years, and currently, there is no effective treatment available. More than 95% of cases are caused by a recurrent mutation (c.617G>A; R206H) of Activin A receptor, type I (ACVR1)/Activin receptor-like kinase-2 (ALK2), a bone morphogenetic protein type I receptor. The mutation renders ACVR1 responsive to activin A, which does not activate wild-type ACVR1. Ectopic activation of ACVR1R206H by activin A induces heterotopic ossification. Since ACVR1R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of mutated ACVR1. To accomplish this goal, we developed locked nucleic acid (LNA) gapmers. These are short DNA oligonucleotides with LNA modification at both ends. They induce targeted mRNA degradation and specific knockdown of gene expression. We demonstrated that some of these gapmers efficiently knocked down ACVR1R206H expression at RNA levels, while ACVR1WT was mostly unaffected in human FOP fibroblasts. Also, the gapmers suppressed osteogenic differentiation induced by ACVR1R206H and activin A. These gapmers may be promising drug candidates for FOP. This novel strategy will also pave the way for antisense-mediated therapy of other autosomal dominant disorders.

Dental management of a 26-year-old female with fibrodysplasia ossificans progressiva: A case report.

PURPOSE: The purpose of the report is to present a rare case of clinical management of a 26-year-old patient with fibrodysplasia ossificans progressiva (FOP), and discuss treatment options and possible outcomes. SUMMARY: FOP is a rare autosomal dominant genetic disorder of the connective tissue that affects one in two million people. It is characterized by multiple areas of progressive heterotopic endochondral ossifications. The symptoms typically begin with painful soft tissue swellings in the patient's first decade, which frequently occur after minor trauma, but may also happen spontaneously. The soft tissue swellings eventually form hard bony masses that cause joint limitations, growth defects, skeletal deformities, and chronic pain. The results are severely limiting to the activities of daily living and overall quality of life with the average life expectancy being 40 years of age. Medical and dental treatment, including the use of general anesthesia, may be complicated by increased risk of ossification of the soft tissues in the airway and lungs. The following case report focuses on a 26-year-old Caucasian female, with FOP. The patient presented to the Erie County Medical Center Dental clinic in Spring 2019 with generalized dental pain. She reported a history of multiple dental infections over many years which were periodically treated with antibiotics. A thorough intraoral exam and radiographs were not able to be completed upon initial presentation due to severe trismus and mobility limitations. The patient was a wheelchair user, verbal, and maintained a completely liquid diet by mouth. The patient also had a medical history significant for dysphagia and aspiration. After a substantial pre-operative optimization process, the patient was brought to the operating room for full mouth dental extractions. At the 2-week follow-up from surgery the patient showed excellent healing. CONCLUSION: While there are greater potential risks with placing a patient with FOP patient under general anesthesia, proper management of dental disease can relieve the patient from recurrent infections and discomfort.

Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics.

Chairside endodontic management of a child with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an exceptionally atypical genetic disorder characterized by heterotopic bone formation within skeletal muscles, ligaments, tendons, and other connective tissues that affects one in 2 million people. A 4-year-old girl with FOP was referred to our practice with complaints of pain and discomfort in both sides of the lower jaw. Clinical examination revealed deep multiple caries and buccal gingival abscess in relation to multiple teeth. Endodontic care and conservative dental procedures were planned and performed chairside after a detailed discussion with FOP medical and dental experts. Very brief dental appointments were conducted with breaks to prevent muscle fatigue. No usage of regional anesthesia or dental dam clamps was done. The patient and her parents were counseled for oral hygiene maintenance, and periodic topical fluoride treatments were performed during successive follow-up appointments. The child is followed for 34 months post-treatment. The dental treatment modifications implemented for the present case were enough to institute good oral health and to prevent the creation of heterotopic ossifications in the maxillofacial region.

Myositis Ossificans of the Adductor Longus in a Soccer Player.

A 20-year-old male collegiate soccer goalkeeper presented to an athletic trainer during the season complaining of right (dominant kicking leg) groin pain. The athletic trainer identified a mass and hematoma and suspected myositis ossificans. The patient was referred to the team physician, who ordered radiographs and magnetic resonance imaging to confirm the diagnosis and rule out other injuries. Imaging demonstrated an adductor longus muscle strain with myositis ossificans. J Orthop Sports Phys Ther 2020;50(10):586. doi:10.2519/jospt.2020.9573.

Rare case of a traumatic myositis ossificans in the tibialis anterior muscle.

Athletes involved in contact sports can be diagnosed with traumatic myositis ossificans. Myositis ossificans is characterised by a benign ossifying lesion in soft tissue mass, most commonly preceded by a muscle contusion in the thigh. Despite the fact that it is often a self-limiting disease, treatment modalities are anti-inflammatory drugs, physiotherapy, shockwave therapy, radiation therapy or surgical resection. We report a 22-year-old competitive football player with severe ongoing pain in the lower leg after a direct trauma. An X-ray showed calcification between the tibia and fibula. An additional ultrasound confirmed the diagnosis: myositis ossificans of the tibialis anterior muscle. After treating him with anti-inflammatory drugs and physiotherapy, he was able to return to sports. Myositis ossificans of the lower leg is an uncommon, though if present, troublesome condition, occurring after a contusion.

Successful Airway and Anesthesia Management Using a High-Flow Nasal Cannula in a Fibrodysplasia Ossificans Progressiva Patient During General Anesthesia: A Case Report.

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disorder causing neck stiffness, ankylosis of temporomandibular joints, and severe restrictive respiratory dysfunction due to progressive heterotopic ossification of the connective tissue. Herein, we report a case of successful airway and anesthesia management using a high-flow nasal cannula (HFNC) in a 51-year-old man with FOP undergoing partial bone resection of the right greater trochanter of the femur. Although general anesthesia with awake fiberoptic nasotracheal intubation has been described as the gold standard, HFNC may yield another potentially viable option for patients undergoing a surgical procedure that does not involve the airway.

Fibrodisplasia osificante progresiva en pediatría: a propósito de un caso clínico / Fibrodysplasia ossificans progressiva in pediatrics: a case report

Introducción: La Fibrodisplasia osificante progresiva es una enfermedad congénita autosómica dominante poco frecuente, caracterizada por malformaciones esqueléticas y osificación heterotópica progresiva e invalidante. Caso clínico: Niño de 11 años consulta por múltiples lesiones osificadas en tronco y región cervical con importante limitación en su movilidad. En el examen físico destaca un ortejo mayor corto. Estudio genético muestra mutación del gen ACVR1. Recibe tratamiento con periodos cortos de corticosteroides posterior a traumas y previo a procedimientos, asociado a un manejo multidisciplinario. Revisión de la literatura: A la fecha el principal tratamiento es la prevención de los brotes de osificación y el uso de corticosteroides o antiinflamatorios cuando los brotes ya se iniciaron. Están en curso ensayos clínicos con bifosfonatos y anticuerpos anti-activina A. Conclusión: En la actualidad no existe un tratamiento específico, sin embargo, un diagnóstico precoz, la prevención de brotes y nuevas terapias podrían mejorar el pronóstico de los pacientes.

ntroduction: Fibrodysplasia ossificans progressiva is a rare autosomal dominant congenital disease characterized by skeletal malformations and progressive disabling heterotopic ossification. Clinical case: An 11-year-old boy consulted with multiple ossified lesions in the trunk and cervical regions associated with significant limitation in mobility. On physical examination, the big toe is short. Genetic study shows ACVR1 gene mutation. He received treatment with short corticosteroid periods after traumas and prior to clinical procedures, as well as a multidisciplinary management.Literature review: To date the main treatment is the prevention of ossification flare-ups and the use of corticosteroids or anti-inflammatories when they have already started. Clinical trials are ongoing with bisphosphonates and anti-activin A antibodies.Conclusion: There is currently no specific treatment, however, early diagnosis, prevention of flare-ups and new therapies could improve the prognosis of patients.

BMP-dependent, injury-induced stem cell niche as a mechanism of heterotopic ossification.

BACKGROUND: Heterotopic ossification (HO), either acquired (aHO) or hereditary, such as fibrodysplasia ossificans progressiva (FOP), is a serious condition without effective treatment. Understanding of the core process of injury-induced HO is still severely limited. METHODS: Double-pulse thymidine analog labeling was used to explore the distinctive domains evolved in injury-induced lesions in an animal model of HO (Nse-BMP4). Histological studies were performed to see whether a similar zonal pattern is also consistently found in biopsies from patients with aHO and FOP. In vivo clonal analysis with Rainbow mice, genetic loss-of-function studies with diphtheria toxin A (DTA)-mediated depletion and lineage tracing with Zsgreen reporter mice were used to obtain further evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells. Immunohistochemistry was used to test whether vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Similar methods also were employed to further understand the signaling pathways that regulate the niche and the resultant HO. RESULTS: We found that distinctive domains evolved in injury-induced lesions, including, from outside-in, a mesenchymal stem cell (MSC) niche, a transient domain and an inner differentiated core in an animal model of HO (Nse-BMP4). A similar zonal structure was found in patients with aHO and FOP. In vivo clonal analysis with Rainbow mice and genetic loss-of-function studies with DTA provided evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells; consistently, vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Further mechanistic study found that BMP and hedgehog (Hh) signaling co-regulate the niche and the resultant HO. CONCLUSIONS: Available data provide evidence of a potential core mechanism in which multiple disease-specific cellular and extracellular molecular elements form a unique local microenvironment, i.e., an injury-induced stem cell niche, which regulates the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs). The implication for HO is that therapeutic approaches must consider several different disease specific factors as parts of a functional unit, instead of treating one factor at a time.

Fibrodysplasia ossificans progressiva - can we diagnose it right at the outset?

Sharma A, Maini D, Agarwal G, Sharma P, Maini L. Fibrodysplasia ossificans progressiva - can we diagnose it right at the outset? Turk J Pediatr 2019; 61: 958-962. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder with no definitive treatment options available yet, except for physiotherapy and bisphosphonates. Due to its initial presentation with multiple lumps in the body, it is often misdiagnosed as a benign tumour most commonly being an osteochondroma or Olliers syndrome. Delay in diagnosis not only delays the management but can also expose the patient to unnecessary interventions. Moreover, earlier diagnosis can also make the patient aware of the precautions to be taken. So our remark is `can we diagnose this disease right at the outset`? We present a case of a 10 year old boy, who had all the classical features of FOP yet was misdiagnosed. Therefore, classical hallmark features of this disease are highlighted in this case report which can be picked up easily by any clinician to reach to a definitive diagnosis as early as possible avoiding unnecessary iatrogenic insult.

Challenges in the treatment of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP), is a rare autosomal dominant connective tissue disease with a prevalence of 1 in 2 million. It is characterized by congenital foot deformities and multiple heterotopic ossifications in fibrous tissue. It usually starts with painful soft tissue swellings occurring with attacks at the ages of three or four. The attacks develop spontaneously or after minor trauma, and gradually turn into heterotopic ossifications that cause joint limitations, growth defects, skeletal deformities and chronic pain. The average life expectancy is forthy, and most of the patients are lost due to pulmonary complications. FOP is often misdiagnosed as fibromatosis, desmoid tumour or cancer, bunion, myositis, arthritis and rheumatic diseases. After clinical suspicion, confirmatory genetic analysis should be used for the diagnosis. The treatment of FOP is currently supportive. An effective, proven method has not yet been established. Herein, we present an 18-year-old female patient with FOP who underwent different treatment modalities in a 5-year period. This case-based review reveals all available treatment approaches with at least 6-month follow-up for FOP in the literature.