Clin Nucl Med 2018 Apr 13. Epub 2018 Apr 13.

A 27-year-old woman had progressive bony ankylosis over both hands since she was 5 years old. Bony ankylosing over the peripheral joints and spine slowly progressed, and scoliosis surgery was performed at age 14. Recently, she developed difficulty walking, changing position, and opening her mouth. Read More

Bone 2018 Apr 4. Epub 2018 Apr 4.

Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX 75246, United States. Electronic address:

Heterotopic ossification (HO), the pathological extraskeletal formation of bone, can arise from blast injuries, severe burns, orthopedic procedures and gain-of-function mutations in a component of the bone morphogenetic protein (BMP) signaling pathway, the ACVR1/ALK2 receptor serine-threonine (protein) kinase, causative of Fibrodysplasia Ossificans Progressiva (FOP). All three ALKs (-2, -3, -6) that play roles in bone morphogenesis contribute to trauma-induced HO, hence are well-validated pharmacological targets. That said, development of inhibitors, typically competitors of ATP binding, is inherently difficult due to the conserved nature of the active site of the 500+ human protein kinases. Read More

Curr Opin Pharmacol 2018 Mar 31;40:51-58. Epub 2018 Mar 31.

Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address:

Heterotopic ossification (HO) involves the formation and accumulation of extraskeletal bone tissue at the expense of local tissues including muscles and connective tissues. There are common forms of HO that are triggered by extensive trauma, burns and other bodily insults, and there are also rare congenital severe forms of HO that occur in children with Fibrodysplasia Ossificans Progressiva or Progressive Osseous Heteroplasia. Given that HO is often preceded by inflammation, current treatments usually involve anti-inflammatory drugs alone or in combination with local irradiation, but are not very effective. Read More

Open Biol 2018 Mar;8(3)

Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan

Rapamycin inhibits TOR (target of rapamycin) kinase, and is being used clinically to treat various diseases ranging from cancers to fibrodysplasia ossificans progressiva. To understand rapamycin mechanisms of action more comprehensively, 1014 temperature-sensitive (ts) fission yeast () mutants were screened in order to isolate strains in which the ts phenotype was rescued by rapamycin. Rapamycin-rescued 45 strains, among which 12 genes responsible for temperature sensitivity were identified. Read More

Int J Mol Sci 2018 Mar 26;19(4). Epub 2018 Mar 26.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is , encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). Read More

Bone 2018 Apr;109:1-2

Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104; Department of Genetics, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104; Department of The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104. Electronic address:

Bone 2018 Mar 15;111:101-108. Epub 2018 Mar 15.

Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Project of Clinical and Basic Research for FOP, Saitama Medical University, Saitama, Japan. Electronic address:

Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2. Read More

BMC Med Genet 2018 Feb 27;19(1):30. Epub 2018 Feb 27.

Department of Emergency Traumatic Surgery, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, People's Republic of China.

Background: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare and disabling genetic disorder of skeletal malformations and progressive heterotopic ossification, is caused by heterozygous activating mutations in activin A receptor, type I/activin-like kinase 2 (ACVR1/ALK2). The rarity of the disease makes it common to make a misdiagnosis and cause mismanagement.

Case Presentation: We reported a case of a sixteen-year-old male patient who had suffered from pain and swelling in the biopsy site for two months. Read More

Skeletal Radiol 2018 Feb 14. Epub 2018 Feb 14.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.

Objective: Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by congenital skeletal deformities and soft tissue masses that progress to heterotopic ossification. Deformities of the great toes are distinctive, and heterotopic ossification in the soft tissues follows an expected anatomic and temporal pattern. In addition to heterotopic ossification, osteochondromata, middle ear ossification, demyelination, lymphedema, and venous thrombosis are characteristic. Read More

Nat Commun 2018 Feb 7;9(1):551. Epub 2018 Feb 7.

Department of Orthopedic Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show that TGF-β initiates and promotes HO in mice. Read More

Bone 2018 Apr 31;109:178-186. Epub 2018 Jan 31.

Department of Molecular & Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT 06269, United States. Electronic address:

Put most simply, heterotopic ossification (HO) is the abnormal formation of bone at extraskeletal sites. HO can be classified into two main subtypes, genetic and acquired. Acquired HO is a common complication of major connective tissue injury, traumatic central nervous system injury, and surgical interventions, where it can cause significant pain and postoperative disability. Read More

Nat Commun 2018 Feb 2;9(1):471. Epub 2018 Feb 2.

Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1 ). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. Read More

Orphanet J Rare Dis 2018 Jan 22;13(1):18. Epub 2018 Jan 22.

Niemann-Pick UK, Suite 2, Vermont House, Concord, Washington, Tyne and Wear, NE37 2SQ, UK.

Background: Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy organization. Biopharmaceutical companies face complex challenges in developing treatments for rare diseases. Read More

Bone 2018 Apr 7;109:56-60. Epub 2018 Jan 7.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Read More

Bone 2018 Apr 4;109:225-231. Epub 2018 Jan 4.

Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

The large majority of cases of the autosomal dominant human disease fibrodysplasia ossificans progressiva (FOP) are caused by gain-of-function Arg206His mutations in the BMP type I receptor ACVR1 (ALK2). The Arg206His mutation is located in the GS domain of the type I receptor. This region is normally phosphorylated by the BMP type II receptor, which activates the type I receptor to phosphorylate its substrate, the signal transducer Smad1/5/8. Read More

Bone 2018 Apr 27;109:201-209. Epub 2017 Dec 27.

Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Read More

Intractable Rare Dis Res 2017 Nov;6(4):242-248

Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, China.

Fibrodysplasia ossificans progressive (FOP) is an extremely rare autosomal dominant disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification that can induce a disabling second skeleton. Spontaneously occurring flare-ups can cause inflammatory soft tissue to swell, followed by progressive and disabling heterotopic endochondral ossification. FOP is very rare, with an estimated incidence of one case per two million individuals. Read More

Bone 2018 Apr 11;109:281-284. Epub 2017 Dec 11.

Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States. Electronic address:

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. Read More

Bone 2018 Apr 11;109:120-123. Epub 2017 Dec 11.

Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States; Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States; The Center for Research in FOP & Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States. Electronic address:

The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Read More

Expert Opin Orphan Drugs 2017 17;5(4):291-294. Epub 2017 Mar 17.

Cali-Weldon Professor of FOP Research; Professor of Orthopaedic Surgery and Genetics, Co-Director, Center for Research in FOP and Related Disorders, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Bone 2018 Apr 22;109:101-103. Epub 2017 Nov 22.

Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address:

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and devastating disorder characterized by cumulative episodes of progressive heterotopic ossification. It is estimated that there exist 600-700 patients in Mainland China. Nevertheless, due to the rarity, many FOP patients were initially misdiagnosed. Read More

Bone 2018 Apr 21;109:218-224. Epub 2017 Nov 21.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Background: Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking.

Objective: To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. Read More

Disabil Rehabil 2017 Nov 16:1-6. Epub 2017 Nov 16.

a Department of Rehabilitation Medicine, Graduate School of Medicine , The University of Tokyo , Tokyo , Japan.

Purpose: Fibrodysplasia ossificans progressiva is a rare congenital disorder that causes systemic heterotopic ossification, leading to systemic ankyloses and mobility losses. This study aimed to ascertain the natural history of fibrodysplasia ossificans progressiva.

Methods: In addition to the medical history questionnaire, patients aged 16 years and older were asked to complete activities of daily living and quality of life surveys using the Barthel Index, MOS 36-Item Short-Form Health Survey, and Health Assessment Questionnaire. Read More

Dev Dyn 2018 Feb 1;247(2):279-288. Epub 2017 Dec 1.

Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Fibrodysplasia Ossificans Progressiva is a rare human disease of heterotopic ossification. FOP patients experience progressive development of ectopic bone within fibrous tissues that contributes to a gradual loss of mobility and can lead to early mortality. Due to lack of understanding of the etiology and progression of human FOP, and the fact that surgical interventions often exacerbate FOP disease progression, alternative therapeutic methods are needed, including modeling in animals, to study and improve understanding of human FOP. Read More

Clin Rheumatol 2018 03;37(3):857

Department of Medical Genetics, National Institute of Health, 27 Avenue Ibn Batouta, BP 769, 11400, Rabat, Morocco.

One of the author's name on this article was incorrectly spelled as "Renata Borcciadi". The correct spelling is "Renata Bocciardi" and is now presented correctly in this article. Read More

Bone 2018 Apr 8;109:192-200. Epub 2017 Nov 8.

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA. Electronic address:

Fibrodysplasia ossificans progressiva (FOP) is a rare bone disease characterized by episodic events of heterotopic ossification (HO). All cases of FOP have been attributed to mutations in the ACVR1 gene that render the encoded BMP type I ALK2 receptor hypersensitive, resulting in the activation of BMP signaling, at inappropriate times in inappropriate locations. The episodic or sporadic nature of HO associated with FOP rests with the occurrence of specific 'triggers' that push the hypersensitive ALK2-FOP receptor into full signaling mode. Read More

J Bone Miner Res 2018 Apr 30;33(4):658-666. Epub 2017 Nov 30.

Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Multiple hereditary exostoses (MHE), also known as multiple osteochondromas (MO), is an autosomal dominant disorder characterized by the development of multiple cartilage-capped bone tumors (osteochondromas). The large majority of patients with MHE carry loss-of-function mutations in the EXT1 or EXT2 gene, which encodes a glycosyltransferase essential for heparan sulfate (HS) biosynthesis. Increasing evidence suggests that enhanced bone morphogenetic protein (BMP) signaling resulting from loss of HS expression plays a role in osteochondroma formation in MHE. Read More

Bone 2018 Apr 31;109:187-191. Epub 2017 Oct 31.

DINOGMI Department, University of Genova, Genova, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, Genova, Italy.

Signaling of the Bone Morphogenetic Protein (BMP) pathway is influenced by the level of expression of its components, in particular receptors, intracellular molecules and target genes which largely depends on gene transcription. One peculiar aspect of Fibrodysplasia Ossificans Progressiva (FOP) relates to the cell types in which the genetic mutation exerts its effects, then not only those involved in the heterotopic ossification processes but also others that participate in the inflammatory phases preceding and triggering heterotopic ossification. Such effects are in part detectable as variation in gene expression, which is also variably manifesting in term of time of appearance in different phases of the inflammatory or ossification processes. Read More

Bone 2018 Apr 31;109:232-240. Epub 2017 Oct 31.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Most patients with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of heterotopic ossification, have the same causative mutation in ACVR1, R206H. However, additional mutations within the ACVR1 BMP type I receptor have been identified in a small number of FOP cases, often in patients with disease of lesser or greater severity than occurs with R206H mutations. Genotype-phenotype correlations have been suggested in patients, resulting in classification of FOP mutations based on location within different receptor domains and structural modeling. Read More

Bone 2018 Apr 13;109:104-110. Epub 2017 Oct 13.

Division of Endocrinology, Diabetes, and Metabolism, Institute for Human Genetics, Department of Medicine, University of California, San Francisco, CA, United States. Electronic address:

Objective: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder in which heterotopic bone forms in the soft tissues. This often occurs in response to injury or inflammation, leading to joint immobilization and significant disability. There are currently no definitive treatment options for this devastating disease. Read More

J Bone Miner Res 2018 Feb 3;33(2):269-282. Epub 2018 Jan 3.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. Read More

Cytometry B Clin Cytom 2017 Oct 6. Epub 2017 Oct 6.

IRCCS Istituto Giannina Gaslini, Genova, Italy.

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder caused by sporadic heterozygous mutations in ACVR1 gene which progressively leads to severe heterotopic ossification. FOP is characterized by episodic flare-ups triggered by different factors such as viral infections, tissue injuries, vaccinations, or occurring without a recognizable cause. The sporadic course of the disease, the documented presence of an important inflammatory reaction in early lesions and the partial response to corticosteroids support the idea that the immune system, and in particular the innate component, may play a role in FOP pathogenesis. Read More

Bone 2018 Apr 28;109:153-157. Epub 2017 Sep 28.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Genesis of a cartilaginous scaffold is an obligate precursor to bone formation in heterotopic endochondral ossification (HEO). We tested the hypothesis that cartilage-derived retinoic acid-sensitive protein (CD-RAP) can serve as a plasma biomarker for the pre-osseous cartilaginous stage of HEO. Palovarotene, a retinoic acid receptor-gamma (RARγ) agonist, has been proposed as a possible treatment for fibrodysplasia ossificans progressiva (FOP) and is a potent inhibitor of HEO in mouse models. Read More

Bone 2018 Apr 21;109:111-114. Epub 2017 Sep 21.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Fibrodyplasia ossificans progressiva (FOP) is an ultra-rare genetic condition of heterotopic ossification (HO) that results in progressive loss of joint function, ultimately rendering movement impossible. Death is most commonly the result of thoracic insufficiency syndrome, or complications related to recurrent respiratory infections. There are no current treatments for FOP, but early and emerging clinical trials offer hope for this devastating disease. Read More

Bone 2018 Apr 12;109:251-258. Epub 2017 Sep 12.

Structural Genomics Consortium, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address:

Individuals with the rare developmental disorder fibrodysplasia ossificans progressiva (FOP) experience disabling heterotopic ossification caused by a gain of function mutation in the intracellular region of the BMP type I receptor kinase ALK2, encoded by the gene ACVR1. Small molecule BMP type I receptor inhibitors that block this ossification in FOP mouse models have been derived from the pyrazolo[1,5-a]pyrimidine scaffold of dorsomorphin. While the first derivative LDN-193189 exhibited pan inhibition of BMP receptors, the more recent compound LDN-212854 has shown increased selectivity for ALK2. Read More

Bone 2018 Apr 1;109:285-290. Epub 2017 Sep 1.

International FOP Association, 1520 Clay St, Suite H2, North Kansas City, MO 64116, USA. Electronic address:

The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntary, observational study that directly captures demographic and disease information initially from patients with FOP (the patient portal) and in the near future from treating physicians (the physician portal) via a secure web-based tool. It was launched by the International FOP Association (IFOPA) with a guiding vision to develop and manage one unified, global, and coordinated Registry allowing the assembly of the most comprehensive data on FOP. This will ultimately facilitate greater access and sharing of patient data and enable better and faster development of therapies and tracking their long-term treatment effectiveness and safety. Read More

J Neurosci 2017 Aug 3;37(35):8524-8533. Epub 2017 Aug 3.

Department of Biology, College of Arts and Sciences, University of New England, Biddeford, Maine 04005,

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Read More

Bone 2018 Apr 26;109:259-266. Epub 2017 Aug 26.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies.

Results: Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Read More

Biochim Biophys Acta 2017 12 25;1864(12):2369-2377. Epub 2017 Aug 25.

Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences and Pharmaceutical Sciences, Nanchang University Medical College, Nanchang, China; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, United States. Electronic address:

Activin A receptor type I or activin receptor-like kinase 2 (ACVRI/ALK2) belongs to type I TGF-β family and plays an important role in bone development. Activating mutations of ALK2 containing the R206 to H mutation, are present in 95% in the rare autosomal genetic disease fibrodysplasia ossificans progressiva (FOP), which leads to the development of ectopic bone formation in muscle. The effect of AMP-activated protein kinase (AMPK) activation on ALK2R206H-mediated signaling in fibroblasts obtained from a FOP patient was assessed in the present study. Read More

Anat Rec (Hoboken) 2018 Jan 12;301(1):56-76. Epub 2017 Sep 12.

Department of Biological Sciences, University of North Texas, 1511 W. Sycamore St, Denton, Texas.

Heterotopic ossification (HO) occurs when soft tissues are inappropriately converted to bony tissue. Several human diseases result in HO with few reliable treatment options. Animal models that naturally produce dermal ectopic bone (i. Read More

Bone 2018 Apr 19;109:267-275. Epub 2017 Aug 19.

Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States. Electronic address:

The majority of skeletal elements develop via endochondral ossification. This process starts with formation of mesenchymal cell condensations at prescribed sites and times in the early embryo and is followed by chondrogenesis, growth plate cartilage maturation and hypertrophy, and replacement of cartilage with bone and marrow. This complex stepwise process is reactivated and recapitulated in physiologic conditions such as fracture repair, but can occur extraskeletally in pathologies including heterotopic ossification (HO), Ossification of the Posterior Longitudinal Ligament (OPLL) and Hereditary Multiple Exostoses (HME). Read More

Bone 2018 Apr 18;109:143-146. Epub 2017 Aug 18.

Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease with a progressive course characterized by episodically local flare-ups, which often but not always leads to heterotopic bone formation (HO). Recently, we showed that [18F]NaF PET/CT may be the first tool to monitor progression of a posttraumatic flare-up leading to new HO, which was demonstrated in a patient with FOP who underwent a maxillofacial surgery. This paper evaluates [18F]NaF PET/CT as a marker of FOP disease activity, comparing its use with other imaging modalities known in literature. Read More

Bone 2018 Apr 16;109:147-152. Epub 2017 Aug 16.

Department of Radiology, Division of Musculoskeletal Imaging and Intervention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States. Electronic address:

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant genetic disorder of heterotopic ossification (HO) characterized by skeletal anomalies and episodic soft tissue swelling (flare-ups) that can transform into heterotopic bone. The progressive development of heterotopic bone and progressive arthropathy leads to significant limitation of mobility. This paper will review various imaging modalities used in evaluating episodic soft tissue swelling (flare-ups), heterotopic bone and skeletal anomalies. Read More

Bone 2018 Apr 16;109:115-119. Epub 2017 Aug 16.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Flare-ups of the hips are among the most feared and disabling complications of fibrodysplasia ossificans progressiva (FOP) and are poorly understood. In order to better understand the nature of hip flare-ups in FOP, we evaluated 25 consecutive individuals with classic FOP (14 males, 11 females; 3-56years old, median age, 17years old) who presented with acute unilateral hip pain.

Results: All 25 individuals were suspected of having a flare-up of the hip based on clinical history and a favorable response to a four day course of high-dose oral prednisone. Read More

Cranio 2017 Aug 11:1-9. Epub 2017 Aug 11.

a FDS, M.S.R.U.A.S., Gnanagangotri Campus , Bengaluru , India.

Background: Trismus is a problem commonly encountered by the dental practitioner. It has a number of potential causes, and its treatment will depend on the cause. However, there are very few reports of trismus due to fibrodysplasia ossificans progressiva (FOP) following third molar surgery. Read More

J Bone Miner Res 2017 Dec 22;32(12):2489-2499. Epub 2017 Sep 22.

Regeneron Pharmaceuticals, Tarrytown, NY, USA.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over a patient's lifetime. FOP is caused by missense mutations in the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined that the formation of heterotopic bone in FOP requires activation of mutant ACVR1 by Activin A, in part by showing that prophylactic inhibition of Activin A blocks HO in a mouse model of FOP. Read More

Bone 2018 Apr 2;109:91-100. Epub 2017 Aug 2.

Division of Neurosurgery, The Children's Hospital of Philadelphia, Colket Translational Research Building Room 4052, 3501 Civic Center Blvd, Philadelphia 19104, PA, United States; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Colket Translational Research Building Room 4052, 3501 Civic Center Blvd, Philadelphia 19104, PA, United States; Center for Data Driven Discovery in Biomedicine, The Children's Hospital of Philadelphia, Colket Translational Research Building Room 4052, 3501 Civic Center Blvd, Philadelphia 19104, PA, United States; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Colket Translational Research Building Room 4052, 3501 Civic Center Blvd, Philadelphia 19104, PA, United States; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, 3501 Civic Center Blvd, Room 4052, Philadelphia 19104, PA, United States. Electronic address:

Gain-of-function mutations in the Type I Bone Morphogenic Protein (BMP) receptor ACVR1 have been identified in two diseases: Fibrodysplasia Ossificans Progressiva (FOP), a rare autosomal dominant disorder characterized by genetically driven heterotopic ossification, and in 20-25% of Diffuse Intrinsic Pontine Gliomas (DIPGs), a pediatric brain tumor with no effective therapies and dismal median survival. While the ACVR1 mutation is causal for FOP, its role in DIPG tumor biology remains under active investigation. Here, we discuss cross-fertilization between the FOP and DIPG fields, focusing on the biological mechanisms and principles gleaned from FOP that can be applied to DIPG biology. Read More

J Clin Invest 2017 Sep 31;127(9):3339-3352. Epub 2017 Jul 31.

Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.

Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Read More

Bone 2018 Apr 25;109:241-250. Epub 2017 Jul 25.

Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.

More than 50years ago, Marshal M. Urist detected "heterotopic bone-inducing activity" in demineralized bone matrix. This unique activity was referred to as "bone morphogenetic protein (BMP)" because it was sensitive to trypsin digestion. Read More

BMJ Case Rep 2017 Jul 27;2017. Epub 2017 Jul 27.

Centro Hospitalar de Lisboa Central EPE, Serviço de Ortopedia - Hospital de Curry Cabral, Lisboa, Portugal.

We report a case of an 18-year-old woman, with bilateral acute inflammatory pain on the hip area, during the premenstrual period, and progressive increase in volume and rigidity of both hips. Bilateral exuberant soft tissue calcifications were present on the radiographic exams, and the patient also presented with bilateral short-length hallux valgus. A heterozygous mutation in the protein kinase domain of gene was found, allowing the diagnosis of fibrodysplasia ossificans progressive. Read More