Fibrodysplasia ossificans progressiva (FOP): A disorder of osteochondrogenesis

Kaplan, Frederick S.; Mukaddam, Mona Al; Stanley, Alexandra; Towler, O. Will; Shore, Eileen M.

doi:10.1016/j.bone.2020.115539

Cited by 37 publications

(43 citation statements)

References 49 publications

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“…Acvr1 is one of the seven known BMP Type I receptors that transduce the extracellular signal to the nucleus (Akhurst et al, 2012; Rigueur et al, 2015;). The gain of function mutation in ACVR1 results in increased pSmad1/5/8, leading to a severe skeletal dysplasia, FOP, which is characterized by severe heterotopic ossification (Kaplan et al, 2020; Meyers et al, 2019). Interestingly, the treatment with a BMP Type I receptor‐specific inhibitor LDN‐193189 resulted in reduced heterotopic ossification in a mouse FOP model (Yu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

The transcriptional cofactor Jab1/Cops5 is crucial for BMP‐mediated mouse chondrocyte differentiation by repressing p53 activity

Mamidi

Samsa

Bashur

et al. 2021

Journal Cellular Physiology

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We previously reported that the evolutionary conserved transcriptional cofactor Jab1/Cops5 is critical for mouse chondrocyte differentiation by selectively repressing BMP signaling. In this study, we first uncovered that the endogenous Jab1 interacts with endogenous Smad1/5/8. Furthermore, although Jab1 did not directly interact with Acvr1 (Alk2), a key Type I BMP receptor, the interaction between endogenous Smad1/5/8 and Acvr1 was increased in Jab1‐null chondrocytes. Thus, Jab1 might negatively regulate BMP signaling during chondrocyte differentiation in part by sequestering Smad1/5/8 away from Acvr1. Next, to identity Jab1 downstream targets in chondrocytes, we performed RNA‐sequencing analysis of Jab1‐null chondrocytes and discovered a total of 1993 differentially expressed genes. Gene set enrichment analysis revealed that key targets inhibited by Jab1 includes p53, BMP/transforming growth factor beta, and apoptosis pathways. We confirmed that endogenous Jab1 interacts with endogenous p53. There was significantly elevated p53 reporter activity, an enhanced expression of phospho‐p53, and an increased expression of a key p53 downstream target, Puma, in Jab1‐null chondrocytes. Moreover, treatments with a p53‐specific inhibitor and/or a BMP Type I receptor‐specific inhibitor reversed the elevated p53 and BMP signaling activities in Jab1‐null chondrocytes and partially restored columnar growth plate structure in E17.5 Jab1‐null mouse tibia explant cultures. Finally, we demonstrated that the chondrocyte‐specific Jab1 overexpression in mice resulted in smaller‐sized embryos with disorganized growth plates. In conclusion, our data showed that the delicate Jab1‐mediated crosstalk between BMP and p53 pathways is crucial to maintain proper chondrocyte survival and differentiation. Moreover, the appropriate Jab1 expression level is essential for proper skeletal development.

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Section: Discussionmentioning

confidence: 99%

The transcriptional cofactor Jab1/Cops5 is crucial for BMP‐mediated mouse chondrocyte differentiation by repressing p53 activity

Mamidi

Samsa

Bashur

et al. 2021

Journal Cellular Physiology

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“…It is commonly misdiagnosed as myositis ossificans and underwent surgical interventions. The diagnosis of FOP is based on three criteria: congenital malformation of the great toes, progressive heterotopic endochondral ossification, and progression of the disease in well-defined anatomical and temporal patterns [4] .…”

Section: Discussionmentioning

confidence: 99%

“…As the disease progresses, the sufferer will become progressively disabled due to extra articular ankylosis in joints throughout the body render restricted or no movement [5] . The jaw region usually is the last to be involved, however, the submandibular area flare up is particularly important as it can lead to difficulty in breathing which can be life threatening [4] . Other complications are deep vein thrombosis, deafness and the most worrisome lung infection.…”

Section: Discussionmentioning

confidence: 99%

Fibrodysplasia Ossificans Progressiva- A case report of exceedingly rare cause of heterotropic ossification

Ng¹,

Ibrahim²,

Ng³

et al. 2021

Hong Kong J Orthop Res

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Fibrodysplasia ossificans progressiva is an exceedingly rare genetic disorder that causes the formation of the second skeleton after birth by the heterotopic bone. It is commonly misdiagnosed and treated inappropriately. Although there is no cure for the disease, early and correct diagnosis may slow the disease progress, avoid unnecessary intervention and in turn improve the quality of life. We report a 13 years old girl with fibrodysplasia ossificans progressiva who presented with progressive stiffness of the bilateral hips after a trivial fall. Further history has found progressive joint stiffness involving multiple joints. She had not been diagnosed even though multiple encounters with the health facility for similar complaints. This has highlighted the importance of awareness of the disease among healthcare personnel.

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“…FOP, a rare genetic disorder with an incidence of one in two million, is characterized by progressive ectopic bone formation in soft tissue (heterotopic ossification (HO)) such as skeletal muscle, tendon, ligament), either spontaneously or after trauma [365] (for review see [366]). ACVR1 mutations do not affect the expression of ALK2 but result in an increase in ALK2 gain of function related to a R206H substitution in the intracellular GS-rich domain of the receptor linked to 95% of the patients [364,367].…”

Section: • Tgf-β Family In Monogenic Developmental Bone Diseasesmentioning

confidence: 99%

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

Jann

Gascon

Roux

et al. 2020

IJMS

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The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors—in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins—not only regulate the proliferation, differentiation, and functioning of these cells, but also coordinate the communication between them to ensure an appropriate response. Therefore, this review focuses on TGF-β superfamily and its influence on bone formation and repair, through the regulation of osteoclastogenesis, osteogenic differentiation of stem cells, and osteoblasts/osteoclasts balance. After introducing the main types of bone cells, their differentiation and cooperation during bone remodeling and fracture healing processes are discussed. Then, the TGF-β superfamily, its signaling via canonical and non-canonical pathways, as well as its regulation by Wnt/Notch or microRNAs are described and discussed. Its important role in bone homeostasis, repair, or disease is also highlighted. Finally, the clinical therapeutic uses of members of the TGF-β superfamily and their associated complications are debated.

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Fibrodysplasia ossificans progressiva (FOP): A disorder of osteochondrogenesis

Cited by 37 publications

References 49 publications

The transcriptional cofactor Jab1/Cops5 is crucial for BMP‐mediated mouse chondrocyte differentiation by repressing p53 activity

The transcriptional cofactor Jab1/Cops5 is crucial for BMP‐mediated mouse chondrocyte differentiation by repressing p53 activity

Fibrodysplasia Ossificans Progressiva- A case report of exceedingly rare cause of heterotropic ossification

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

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