scholarly journals Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva

2018 ◽  
Vol 33 (2) ◽  
pp. 269-282 ◽  
Author(s):  
Michael R Convente ◽  
Salin A Chakkalakal ◽  
EnJun Yang ◽  
Robert J Caron ◽  
Deyu Zhang ◽  
...  
Keyword(s):  
Mast Cells ◽  
Mouse Model ◽  
Heterotopic Ossification ◽  
Fibrodysplasia Ossificans Progressiva

scholarly journals Response to comment on 'Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity'

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
David J Goldhamer ◽  
John B Lees-Shepard
Keyword(s):  
Side Effects ◽  
Mouse Model ◽  
Heterotopic Ossification ◽  
Fibrodysplasia Ossificans Progressiva

We respond to concerns expressed by Pacifici and Shore (2019) about a recent paper (Lees-Shepard and Goldhamer, 2018a) in which we reported that the drug palovarotene can have severe side effects in a mouse model of fibrodysplasia ossificans progressiva.

An Acvr1[R258G] ‘conditional on' mouse model of atypical fibrodysplasia ossificans progressiva (FOP) is Activin A dependent

2019 ◽  
Author(s):  
Lily Huang ◽  
Chris Schoenherr ◽  
Lili Wang ◽  
Xialing Wen ◽  
Joyce McClain ◽  
...  
Keyword(s):  
Mouse Model ◽  
Activin A ◽  
Fibrodysplasia Ossificans Progressiva

scholarly journals MyD88 Is Not Required for Muscle Injury-Induced Endochondral Heterotopic Ossification in a Mouse Model of Fibrodysplasia Ossificans Progressiva

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 630
Author(s):  
Huili Lyu ◽  
Cody M. Elkins ◽  
Jessica L. Pierce ◽  
C. Henrique Serezani ◽  
Daniel S. Perrien
Keyword(s):  
Heterotopic Ossification ◽  
Muscle Injury ◽  
Cell Types ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Inflammatory Signaling ◽  
Conditional Deletion ◽  
Pathway Crosstalk ◽  
Multiple Cell

Excess inflammation and canonical BMP receptor (BMPR) signaling are coinciding hallmarks of the early stages of injury-induced endochondral heterotopic ossification (EHO), especially in the rare genetic disease fibrodysplasia ossificans progressiva (FOP). Multiple inflammatory signaling pathways can synergistically enhance BMP-induced Smad1/5/8 activity in multiple cell types, suggesting the importance of pathway crosstalk in EHO and FOP. Toll-like receptors (TLRs) and IL-1 receptors mediate many of the earliest injury-induced inflammatory signals largely via MyD88-dependent pathways. Thus, the hypothesis that MyD88-dependent signaling is required for EHO was tested in vitro and in vivo using global or Pdgfrα-conditional deletion of MyD88 in FOP mice. As expected, IL-1β or LPS synergistically increased Activin A (ActA)-induced phosphorylation of Smad 1/5 in fibroadipoprogenitors (FAPs) expressing Alk2R206H. However, conditional deletion of MyD88 in Pdgfrα-positive cells of FOP mice did not significantly alter the amount of muscle injury-induced EHO. Even more surprisingly, injury-induced EHO was not significantly affected by global deletion of MyD88. These studies demonstrate that MyD88-dependent signaling is dispensable for injury-induced EHO in FOP mice.

scholarly journals POS0083 USEFUL EXPERIENCE OF RHEUMATOLOGISTS FOR UNDERSTANDING OF THE DISEASE ORIGIN AND APPROACHES TO THERAPY IN FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 249.2-250
Author(s):  
I. Nikishina ◽  
S. Arsenyeva ◽  
V. Matkava ◽  
A. Arefieva ◽  
M. Kaleda ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Kinase Inhibitor ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Rapid Progression ◽  
Time Duration ◽  
Long Term Follow Up ◽  
Vertebral Bodies ◽  
The One

Background:Many monogenic genetic conditions, such as auto-inflammatory diseases (AIDs), have similar clinical manifestations and immunopathogenesis to “classic” rheumatic diseases (RD). Such cases may include Fibrodysplasia ossificans progressiva (FOP), an extremely rare genetic disease, which, according to our previous study and data from other authors1, may represent an example of AID with catastrophic heterotopic ossification due to a mutation in the ACVR1 gene. it seems that the experience of rheumatologists, especially children’s ones, will be useful in the treatment of FOP.Objectives:To analyzed the dynamics of clinical manifestations and to therapy approaches including target anti-inflammatory drug Tofacitinib (TOFA) in the one of the world’s largest groups of patients (pts) with FOP.Methods:The study was based on the analysis retrospective and prospective observation of the 35 pts (17 males and 18 females) with a verified diagnosis of FOP for the period from 1998 to 2020. In 9 pts with severe course of FOP TOFA administration were evaluated.Results:In all 35 pts the diagnosis was verified by “classic” FOP phenotype: malformed great toes in 33 pts (94,3%); short malformed thumbs-8 (22.8%); peripheral osteochondromas-20 (57.1%); abnormalities of the cervical spine-32 (91.4%), multiple heterotopic ossifications-32 (91,4%). Genetic tests were done in 26, it confirmed mutation in the ACVR1 gene in 100%. Long term follow-up detected a lot of spondyloarthritis-like signs similar to the manifestation of RD: ankylosis of the facet joints and vertebral bodies (by the type of syndesmophytes) in most pts, sacroiliitis, confirmed by radiological methods (X-ray, CT, MRI), gradual ankylosis in the peripheral joints in 18 (56.4%), synovitis in large joints in 8 (25%) pts (knee and hip mostly). In 9 pts with the most difficult course with rapid progression of ossification due to continuous flares despite the NSAIDs and steroids intake, we tried to use TOFA after the approval of the local Ethic Committee. We use the similar dose to randomized trial for JIA (up to 5 mg twice a day). The first patient was 16 y.o. at the time of TOFA administration in December 2019, the age of the other pts was from 2 to 12 y.o. By present time duration of TOFA therapy is from 6 to 15 mo. For the previous 6 months before TOFA initiation the number of flares was in average 8 per patient. After 6 months of TOFA treatment the number of new flares decreased to 0-1, except youngest patient of 2 y.o. in whom the number of flares decreased from 10 to 4 per the same period. In all 9 pts we minimize the dose or completely stop the steroids. New nodes formation stopped immediately in most pts and also the significant motion improvement of large (shoulder) joints were established. Drug tolerance was good in all pts, no AE were registered. But despite the good clinical effect without new heterotopic ossification in our first patient, we found continuous intraskeletal ossification between vertebral bodies, facet and sacroiliac joints in MRI.Conclusion:We are confident that the processes of heterotopic ossification in FOP are very similar to new born formation phenomenon in spondyloarthritis and reliable suppression of inflammation can interrupt the progression of the disease. We used similar justifications to our colleagues for the use of anti-cytokine drugs, but used a JAK-kinase inhibitor, it was extremely important the oral rout of drug administration and possibility to escape any injections in FOP. TOFA demonstrated positive effect and safety in children with severe course of FOP. It showed their advantages over the use of steroids and possibility to inhibit the rate of progression.References:[1]R.Haviv et al. Is fibrodysplasia ossificans progressiva aninterleukin-1 driven auto-inflammatory syndrome? Pediatric Rheumatology (2019) 17:84 //doi.org/10.1186/s12969-019-0386-6Disclosure of Interests:None declared.

scholarly journals High-frequency spectral ultrasound imaging (SUSI) visualizes early post-traumatic heterotopic ossification (HO) in a mouse model

Bone ◽  
2018 ◽  
Vol 109 ◽  
pp. 49-55 ◽  
Author(s):  
Kavitha Ranganathan ◽  
Xiaowei Hong ◽  
David Cholok ◽  
Joe Habbouche ◽  
Caitlin Priest ◽  
...  
Keyword(s):  
Mouse Model ◽  
Heterotopic Ossification ◽  
Ultrasound Imaging ◽  
High Frequency ◽  
Post Traumatic

scholarly journals Opioid signaling in mast cells regulates injury responses associated with heterotopic ossification

2013 ◽  
Vol 63 (3) ◽  
pp. 207-215 ◽  
Author(s):  
Lixin Kan ◽  
Amelia A. Mutso ◽  
Tammy L. McGuire ◽  
Apkar Vania Apkarian ◽  
John A. Kessler
Keyword(s):  
Mast Cells ◽  
Heterotopic Ossification ◽  
Opioid Signaling

Effects of blockade of endogenous Gisignaling in Tie2-expressing cells on bone formation in a mouse model of heterotopic ossification

2015 ◽  
Vol 33 (8) ◽  
pp. 1212-1217 ◽  
Author(s):  
Liping Wang ◽  
Dylan O' Carroll ◽  
Xuhui Liu ◽  
Theresa Roth ◽  
Hubert Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bone Formation ◽  
Heterotopic Ossification

Anti-allergic function of α-Tocopherol is mediated by suppression of PI3K-PKB activity in mast cells in mouse model of allergic rhinitis

2020 ◽  
Vol 48 (4) ◽  
pp. 395-400
Author(s):  
Geping Wu ◽  
Hongyan Zhu ◽  
Xinyang Wu ◽  
Lili Liu ◽  
Xingkai Ma ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Mast Cells ◽  
Mouse Model

scholarly journals Clinical Aspects and Current Therapeutic Approaches for FOP

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 325
Author(s):  
Hiroshi Kitoh
Keyword(s):  
Heterotopic Ossification ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Clinical Aspects ◽  
Type I ◽  
Gene Encoding ◽  
Neck Stiffness ◽  
Skeletal Malformations ◽  
Morphogenetic Protein ◽  
Heritable Disorder ◽  
Ossification Centers

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare heritable disorder of connective tissues characterized by progressive heterotopic ossification in various skeletal sites. It is caused by gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1)/activin-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Heterotopic ossification is usually progressive leading to severe deformities in the trunk and extremities. Early clinical diagnosis is important to prevent unnecessary iatrogenic harm or trauma. Clinicians should become aware of early detectable skeletal malformations, including great toe deformities, shortened thumb, neck stiffness associated with hypertrophy of the posterior elements of the cervical spine, multiple ossification centers in the calcaneus, and osteochondroma-like lesions of the long bones. Although there is presently no definitive medical treatment to prevent, stop or reverse heterotopic ossification in FOP, exciting advances of novel pharmacological drugs focusing on target inhibition of the activated ACVR1 receptor, including palovarotene, REGN 2477, rapamycin, and saracatinib, have developed and are currently in clinical trials.

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