Bmp Signaling In Fibrodysplasia Ossificans Progressiva A Springer

Leo Migdal

-Dec 5, 2025, 8:36 PM

bmp signaling in fibrodysplasia ossificans progressiva a springer

Part of the book series: Progress in Inflammation Research ((PIR)) Heterotopic ossification (HO), the formation of extraskeletal bone, is most frequently associated with severe tissue injury. However, predicting who will be susceptible to HO and when HO will form has been challenging, resulting in a paucity of information about the causes and progression of this heterotopic bone formation. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which heterotopic bone forms in soft connective tissues during childhood and throughout adult life, frequently in response to tissue trauma. The discovery that FOP is caused by gain-of-function mutations in ACVR1, the gene encoding the ALK2 BMP type I receptor, established that perturbation in the bone morphogenetic protein (BMP) signaling pathway is an underlying... The identification of the responsible gene for FOP, together with the development of animal models for HO and FOP, is now leading to advances in understanding the cellular and molecular mechanisms of bone formation...

This is a preview of subscription content, log in via an institution to check access. Tax calculation will be finalised at checkout Shore EM, Kaplan FS (2010) Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6(9):518–527 O. Will Towler: Conceptualization; writing-original draft; writing-review & editing.

Eileen Shore: Conceptualization; funding acquisition; project administration; writing-original draft; writing-review & editing. Correspondence: Eileen M. Shore, The Center for Research in FOP & Related Disorders, University of Pennsylvania, Philadelphia, PA, USA. shore@pennmedicine.upenn.edu Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disease caused by increased BMP pathway signaling due to mutation of ACVR1, a bone morphogenetic protein (BMP) type 1 receptor. The primary clinical manifestation of FOP is extra-skeletal bone formation (heterotopic ossification) within soft connective tissues.

However, the underlying ACVR1 mutation additionally alters skeletal bone development and nearly all people born with FOP have bilateral malformation of the great toes as well as other skeletal malformations at diverse anatomic sites. The specific mechanisms through which ACVR1 mutations and altered BMP pathway signaling in FOP influence skeletal bone formation during development remain to be elucidated; however, recent investigations are providing a clearer understanding of the... Keywords: ACVR1, bone morphogenetic protein, fibrodysplasia ossificans progressiva, FOP, heterotopic ossification, joint development, toe/digit malformation Skeletal tissues are essential to the structure, locomotion, and protection of the body. Bone provides body structure, encases and protects soft organs as the skull does for the brain, and supports the physical interactions of the body with its environment such as the fine, complex manipulations by... By mineralizing a carefully patterned skeletal template during embryogenesis and leaving unmineralized segments (ie, the joints) to permit mobility and flexibility, organisms acquire a stable framework capable of highly specialized structures, movements, and functions.

Disrupting this patterning and the processes of cell differentiation and mineralization can lead to too much or too little bone, which in turn leads to alterations in the shape or positions of the skeletal... For example, bone that spans a joint, whether within the joint or bridging the two adjacent bones, will lock these elements in place and prevent mobility. Thus, the processes of patterning skeletal elements, ossifying bone tissue, and maintaining material properties are all critical to the successful development and function of the skeleton. Address reprint requests to: Frederick S Kaplan, MD The University of Pennsylvania School of Medicine Department of Orthopaedic Surgery Hospital of the University of Pennsylvania Silverstein 2, 3400 Spruce Street Philadelphia, PA 19104, USA... Received 2007 Jun 14; Revised 2007 Aug 28; Accepted 2007 Oct 26; Issue date 2008 Mar. The study of FOP, a disabling genetic disorder of progressive heterotopic ossification, is hampered by the lack of readily available connective tissue progenitor cells.

We isolated such cells from discarded primary teeth of patients with FOP and controls and discovered dysregulation of BMP signaling and rapid osteoblast differentiation in FOP cells compared with control cells. Fibrodysplasia ossificans progressiva (FOP), the most disabling condition of progressive heterotopic ossification in humans, is caused by a recurrent heterozygous missense mutation in activin receptor IA (ACVR1), a bone morphogenetic protein (BMP) type I... A comprehensive understanding of FOP has been limited, in part, by a lack of readily available connective tissue progenitor cells in which to study the molecular pathology of this disorder. We derived connective tissue progenitor cells from discarded primary teeth (SHED cells) of patients with FOP and controls and examined BMP signaling and osteogenic differentiation in these cells. You have full access to this open access article A News & Views to this article was published on 03 December 2024

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. Early-stage FOP is characterized by recurrent episodes of painful tissue swelling (flare-ups), with numerous proliferation-activated mesenchymal stromal cells (MSCs) subsequently causing HO. However, the mechanisms underlying flare-up progression remain unclear. In this study, we evaluated the proliferation of MSCs obtained from FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to elucidate the mechanisms underlying flare-ups and found that bone morphogenetic protein (BMP)-9 mediated enhanced proliferation... In FOP model mice, elevated BMP-9 levels correlated with elevated phosphorylation of SMAD2/3 and increased cellular proliferation in the affected tissues, while systemic BMP-9 neutralization and knockout mitigated flare-ups and HO. Thus, BMP-9 aberrantly transduces TGF-β signaling and induces fibroproliferation, initiating flare-ups.

This study provides novel insights into the development of future FOP therapies. To uncover the mechanism of fibroproliferative tissue formation in early-stage fibrodysplasia ossificans progressiva (FOP), mesenchymal stromal cells (MSCs) from patient-derived induced pluripotent stem cells and FOP model mice carrying the human ACVR1 (R206H) allele... Bone morphogenetic protein (BMP)-9 aberrantly enhances both the cell proliferation rate and the transforming growth factor (TGF)-β signaling pathway in MSCs derived from FOP patient-derived induced pluripotent stem cells (FOP-iPSCs). Address correspondence to: Michael T Collins, NIH, 30 Convent Drive, Building 30, Room 228, MSC 4320, Bethesda, Maryland 20892-4320, USA. Phone: 301.728.0329; Email: mcollins@dir.nidcr.nih.gov. Issue date 2022 Jun 15; Collection date 2022 Jun 15.

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Fibrodysplasia ossificans progressiva (FOP) is an ultrarare, debilitating disease in which heterotopic bone is formed in certain soft tissues. A gain-of-function variant in the cytoplasmic domain of the activin A receptor type I (ACVR1) exists in all patients with FOP. Strikingly, these FOP-causing variants imbue a neofunction to ACVR1 — the ability to recognize activin A as an agonist with bone morphogenic protein–like signaling that leads to heterotopic ossification (HO). These findings are supported by the efficacy of anti–activin A antibodies in preventing HO in FOP mice.

This surprising story continues in companion papers in this issue of the JCI. Aykul et al. and Lees-Shepard et al. independently found that antibodies against ACVR1, which were being developed as potential therapeutics for FOP, instead caused HO in FOP mice. While this unexpected finding may be the clinical final act for such antibodies, it provides another twist in the unique and evolving FOP story. Fibrodysplasia ossificans progressiva (FOP, identified as OMIM #135100) is an insidious and devastating disease in which there can be massive heterotopic bone formation.

Small foci of heterotopic endochondral bone, often stimulated by minor trauma, first appear in childhood. Lesions multiply, coalesce, expand, and mature into a mixture of woven and lamellar bone (1), eventually leading to the patient effectively being locked-in with progressive loss of mobility (2). Early mortality, corresponding to a median survival of 45 years, is most often due to cardiorespiratory failure from heterotopic bone–induced thoracic insufficiency syndrome (3). Treatment for FOP represents a tremendous unmet need; there are no globally approved therapies. You have full access to this open access article An Article was published on 03 December 2024

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized primarily by the formation of heterotopic bone in connective tissue, such as tendon, muscle, ligament and fascia (Kaplan et al, 2024). The prevalence is approximately one in 2.5 million births, with over 2,500 cases diagnosed globally. Although rare, FOP is a severe and life-limiting condition with no current cure. Due to heterotopic bone formation in various organs, patients experience intense pain, restricted mobility, difficulty with eating and speaking, hearing loss, scoliosis, and impaired pulmonary function. The average lifespan for individuals with FOP is around 40 years. Therefore, studying the pathological mechanism and developing efficient drugs for FOP are highly demanding.

In this issue of EMBO Molecular Medicine, Zhao et al, introduce bone morphogenetic protein 9 (BMP9) as a potential therapeutic target for FOP (Zhao et al, 2024). Avoid common mistakes on your manuscript. Heterotopic ossification (HO) initiates in response to trauma or injury to soft tissue, beginning with a painful swelling known as a flare-up. Flare-ups progress through three stages: muscle degeneration, inflammatory infiltration, and fibroproliferation, which together can last for several weeks. Following these stages, the process of endochondral bone formation often occurs at the flare-up site, where chondrocytes develop and gradually calcify into ectopic bone tissue. These flare-ups can recur, progressively debilitating patients over their lifetime (Pignolo et al, 2016).

Bmp Signaling In Fibrodysplasia Ossificans Progressiva A Springer

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Eileen Shore: Conceptualization; Funding Acquisition; Project Administration; Writing-original Draft; Writing-review

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