Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. Children who have FOP appear normal at birth except for congenital malformations of the great toes. During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features [FOP plus], or present with major variations in one or both of the two classic defining features of FOP [FOP variants]. Classic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids. The diagnosis of FOP is made by clinical evaluation. Confirmatory genetic testing is available. Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification. Although most cases of FOP are sporadic (noninherited mutations), a small number of inherited FOP cases show germline transmission in an autosomal dominant pattern. At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls, respiratory decline, and viral infections. The median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome

Diabetes Reduces Mesenchymal Stem Cells in Fracture Healing Through a TNFα-Mediated Mechanism

Aims/hypothesis Diabetes interferes with bone formation and impairs fracture healing, an important complication in humans and animal models. The aim of this study was to examine the impact of diabetes on mesenchymal stem cells (MSCs) during fracture repair. Methods Fracture of the long bones was induced in a streptozotocin-induced type 1 diabetic mouse model with or without insulin or a specific TNFα inhibitor, pegsunercept. MSCs were detected with cluster designation-271 (also known as p75 neurotrophin receptor) or stem cell antigen-1 (Sca-1) antibodies in areas of new endochondral bone formation in the calluses. MSC apoptosis was measured by TUNEL assay and proliferation was measured by Ki67 antibody. In vitro apoptosis and proliferation were examined in C3H10T1/2 and human-bone-marrow-derived MSCs following transfection with FOXO1 small interfering (si)RNA. Results Diabetes significantly increased TNFα levels and reduced MSC numbers in new bone area. MSC numbers were restored to normal levels with insulin or pegsunercept treatment. Inhibition of TNFα significantly reduced MSC loss by increasing MSC proliferation and decreasing MSC apoptosis in diabetic animals, but had no effect on MSCs in normoglycaemic animals. In vitro experiments established that TNFα alone was sufficient to induce apoptosis and inhibit proliferation of MSCs. Furthermore, silencing forkhead box protein O1 (FOXO1) prevented TNFα-induced MSC apoptosis and reduced proliferation by regulating apoptotic and cell cycle genes. Conclusions/interpretation Diabetes-enhanced TNFα significantly reduced MSC numbers in new bone areas during fracture healing. Mechanistically, diabetes-enhanced TNFα reduced MSC proliferation and increased MSC apoptosis. Reducing the activity of TNFα in vivo may help to preserve endogenous MSCs and maximise regenerative potential in diabetic patients

Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling

Hypoxia and inflammation are implicated in the episodic induction of heterotopic endochondral ossification (HEO); however, the molecular mechanisms are unknown. HIFâ 1α integrates the cellular response to both hypoxia and inflammation and is a prime candidate for regulating HEO. We investigated the role of hypoxia and HIFâ 1α in fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of HEO in humans. We found that HIFâ 1α increases the intensity and duration of canonical bone morphogenetic protein (BMP) signaling through Rabaptin 5 (RABEP1)â mediated retention of Activin A receptor, type I (ACVR1), a BMP receptor, in the endosomal compartment of hypoxic connective tissue progenitor cells from patients with FOP. We further show that early inflammatory FOP lesions in humans and in a mouse model are markedly hypoxic, and inhibition of HIFâ 1α by genetic or pharmacologic means restores canonical BMP signaling to normoxic levels in human FOP cells and profoundly reduces HEO in a constitutively active Acvr1Q207D/+ mouse model of FOP. Thus, an inflammation and cellular oxygenâ sensing mechanism that modulates intracellular retention of a mutant BMP receptor determines, in part, its pathologic activity in FOP. Our study provides critical insight into a previously unrecognized role of HIFâ 1α in the hypoxic amplification of BMP signaling and in the episodic induction of HEO in FOP and further identifies HIFâ 1α as a therapeutic target for FOP and perhaps nongenetic forms of HEO. © 2016 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134262/1/jbmr2848_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134262/2/jbmr2848.pd

Brief Report: Long‐Term Functional Engraftment of Mesenchymal Progenitor Cells in a Mouse Model of Accelerated Aging

Age‐related osteoporosis is characterized by a decrease in bone‐forming capacity mediated by defects in the number and function of osteoblasts. An important cellular mechanism that may in part explain osteoblast dysfunction that occurs with aging is senescence of mesenchymal progenitor cells (MPCs). In the telomere‐based Wrn −/− Terc −/− model of accelerated aging, the osteoporotic phenotype of these mice is also associated with a major decline in MPC differentiation into osteoblasts. To investigate the role of MPC aging as a cell‐autonomous mechanism in senile bone loss, transplantation of young wild‐type whole bone marrow into Wrn −/− Terc −/− mutants was performed and the ability of engrafted cells to differentiate into cells of the osteoblast lineage was assessed. We found that whole bone marrow transplantation in Wrn −/− Terc −/− mice resulted in functional engraftment of MPCs up to 42 weeks, which was accompanied by a survival advantage as well as delays in microarchitectural features of skeletal aging. S TEM C ELLS 2013;31:607–611Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/1/sc-12-0760_sm_SupplFigure1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/2/1294_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/3/sc-12-0760_sm_SupplFigure2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/4/sc-12-0760_sm_SupplFigure3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96667/5/sc-12-0760_sm_SupplInform.pd

Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective

Background Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of soft and connective tissues. Assiduous attention to the unmet needs of this patient community is crucial to prevent potential iatrogenic harm and optimize care for individuals with FOP. Objective To gather international expert opinion and real-world experience on the key challenges for individuals with FOP and their families, highlight critical gaps in care, communication, and research, and provide recommendations for improvement. Methods An international group of expert clinicians, patients and patient advocates, caregivers and representatives from the international FOP community participated in a virtual, half-day meeting on 22 March 2021 to discuss the key unmet needs of individuals with FOP. Results Individuals with FOP often face the frustration of long diagnostic journeys, the burden of self-advocacy and the navigation of novel care pathways. Globally, patients with FOP are also confronted with inequities in access to diagnosis and specialist care, and consequently, unequal access to registries, clinical trials, and essential support from patient associations. Organizations such as the International FOP Association, the International Clinical Council on FOP, and national FOP organizations work to provide information, facilitate access to expert clinical guidance, nurture patient empowerment, fund FOP research and/or foster meaningful collaborations with the research community. The non-profit Tin Soldiers Global FOP Patient Search program aims to identify and provide a pathway to diagnosis and care for individuals with FOP, particularly in underserved communities. Such global initiatives and the increasingly widespread use of telemedicine and digital platforms offer opportunities to improve vital access to care and research. Conclusions This multi-stakeholder perspective highlights some of the unmet needs of individuals with FOP and their families. Regional and international organizations play an important role in improving the quality of life of those they reach in the global FOP community. However, globally, fundamental issues remain around raising awareness of FOP among healthcare professionals, identifying individuals with FOP, reducing time to diagnosis, and ensuring access to best practice in care, support, and clinical research. Medical writing support was industry-sponsored

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

Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP).

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials

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\u27s 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

DNA Methyltransferase Controls Stem Cell Aging by Regulating BMI1 and EZH2 through MicroRNAs

Epigenetic regulation of gene expression is well known mechanism that regulates cellular senescence of cancer cells. Here we show that inhibition of DNA methyltransferases (DNMTs) with 5-azacytidine (5-AzaC) or with specific small interfering RNA (siRNA) against DNMT1 and 3b induced the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) and increased p16INK4A and p21CIP1/WAF1 expression. DNMT inhibition changed histone marks into the active forms and decreased the methylation of CpG islands in the p16INK4A and p21CIP1/WAF1 promoter regions. Enrichment of EZH2, the key factor that methylates histone H3 lysine 9 and 27 residues, was decreased on the p16INK4A and p21CIP1/WAF1 promoter regions. We found that DNMT inhibition decreased expression levels of Polycomb-group (PcG) proteins and increased expression of microRNAs (miRNAs), which target PcG proteins. Decreased CpG island methylation and increased levels of active histone marks at genomic regions encoding miRNAs were observed after 5-AzaC treatment. Taken together, DNMTs have a critical role in regulating the cellular senescence of hUCB-MSCs through controlling not only the DNA methylation status but also active/inactive histone marks at genomic regions of PcG-targeting miRNAs and p16INK4A and p21CIP1/WAF1 promoter regions