Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

Fukuda, Tsuyoshi; Kohda, Masakazu; Kanomata, Kazuhiro; Nojima, Junya; Nakamura, Atsushi; Kamizono, Jyunji; Noguchi, Yasuo; Iwakiri, K.; Kondo, Takeo; Kurose, Junichi; Endo, Kenichi; Awakura, Takeshi; Fukushi, Jun-ichi; Nakashima, Yasuharu; Chiyonobu, Tomohiro; Kawara, Akira; Nishida, Yoshihiro; Wada, Ikuo; Akita, Masumi; Komori, Tetsuo; Nakayama, Konosuke; Nanba, Akira; Maruki, Yuichi; Yoda, Tetsuya; Tomoda, Hiroshi; Yu, Paul B.; Shore, Eileen M.; Kaplan, Frederick S.; Miyazono, Kohei; Matsuoka, Makoto; Ikebuchi, Kenji; Ohtake, Akira; Oda, Hiromi; Jimi, Eijiro; Owan, Ichiro; Okazaki, Yasushi; Katagiri, Takenobu

doi:10.1074/jbc.m801681200

Cited by 187 publications

(186 citation statements)

References 43 publications

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“…1A). Consistent with previous reports (14,18), several BMP ligands, such as BMP-6 and BMP-7, induced higher luminescence in FOP-iMSCs than resFOP-iMSCs, but at less than 1.4-fold ( Fig. 1B and SI Appendix, Fig.…”

Section: Activin-a Abnormally Transduced Bmp Signaling In Fop-imscs Butsupporting

confidence: 79%

“…ACVR1 mutations in atypical FOP patients have been found also in other amino acids of the GS domain or protein kinase domain (11,12). Regardless of the mutation site, mutated ACVR1 (FOP-ACVR1) has been shown to activate BMP signaling without exogenous BMP ligands (constitutive activity) and transmit much stronger BMP signaling after ligand stimulation (hyperactivity) (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

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confidence: 99%

“…To reveal the molecular nature of how FOP-ACVR1 activates BMP signaling, cells overexpressing FOP-ACVR1 (12)(13)(14)(15)(16)(17)(18)(19)(20), mouse embryonic fibroblasts derived from Alk2 R206H/+ mice (21,22), and cells from FOP patients, such as stem cells from human exfoliated deciduous teeth (23), FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) (24,25) and induced mesenchymal stromal cells (iMSCs) from FOP-iPSCs (FOP-iMSCs) (26) have been used as models. Among these cells, Alk2 R206H/+ mouse embryonic fibroblasts and FOP-iMSCs are preferred because of their accessibility and expression level of FOP-ACVR1 using an endogenous promoter.…”

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confidence: 99%

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Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

Hino

Ikeya

Horigome

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

248

306

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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and liganddependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOPiPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP.iPSC | fibrodysplasia ossificans progressiva | heterotopic ossification | BMP | TGF H eterotopic ossification (HO) is defined as bone formation in soft tissue where bone normally does not exist. It can be the result of surgical operations, trauma, or genetic conditions, one of which is fibrodysplasia ossificans progressiva (FOP). FOP is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification (1-6). The responsive mutation for classic FOP is 617G > A (R206H) in the intracellular glycineand serine-rich (GS) domain (7) of ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP) (8-10). ACVR1 mutations in atypical FOP patients have been found also in other amino acids of the GS domain or protein kinase domain (11,12). Regardless of the mutation site, mutated ACVR1 (FOP-ACVR1) has been shown to activate BMP signaling without exogenous BMP ligands (constitutive activity) and transmit much stronger BMP signaling after ligand stimulation (hyperactivity) (12-25).To reveal the molecular nature of how FOP-ACVR1 activates BMP signaling, cells overexpressing FOP-ACVR1 (12-20), mouse embryonic fibroblasts derived from Alk2 R206H/+ mice (21, 22), and cells from FOP patients, such as stem cells from human exfoliated deciduous teeth (23), FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) (24, 25) and induced mesenchymal stromal cells (iMSCs) from FOP-iPSCs (FOP-iMSCs) (26) have been used as models. Among these cells, Alk2 R206H/+ mouse embryonic fibroblasts and FOP-iMSCs are preferred because of their accessibility and expression level of FOP-ACVR1 using an endogenous promoter. In these cells, however, the constitutive activity and hyperactivity is not strong (within twofold normal levels) (22,26). In addition, despite the essential role of BMP signaling in development (27-31), the pre-and postnatal development and growth of FOP patients are almost normal, and H...

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Section: Activin-a Abnormally Transduced Bmp Signaling In Fop-imscs Butsupporting

confidence: 79%

mentioning

confidence: 99%

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confidence: 99%

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Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

Hino

Ikeya

Horigome

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

248

306

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“…1,2,4 The pathogenic, mutant ALK2 receptor appears to be a highly sensitive bone morphogenetic protein (BMP) type I receptor to BMPs and external triggers, resulting in an apparently constitutively active ALK2 receptor, and thereby readily inducing heterotopic bone formation in FOP. 5,6 Currently, there is no definitive treatment of FOP. Chemical inhibitors against the pathogenic (constitutively active) ALK2 receptors have been developed and could be possible medical agents for FOP.…”

Section: Introductionmentioning

confidence: 99%

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

et al. 2011

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Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant congenital disorder characterized by progressive heterotopic bone formation. Currently, no definitive treatment exists for FOP. The activin receptor type IA / activin-like kinase 2 (ACVR1/ALK2) gene has been identified as the responsible gene for FOP, and disease-associated ALK2 mutations have been found. Chemical inhibitors to the pathogenic ALK2 receptors are considered possible medical agents for FOP, but their adverse effects on normal ALK2 and other receptors cannot be excluded. Here we describe another treatment strategy for FOP using allele-specific RNA interference (ASP-RNAi), and show modified small interfering RNAs (siRNAs) conferring allele-specific silencing against disease-causing ALK2 mutants found in FOP, without affecting normal ALK2 allele. Thus, the siRNAs presented here may become novel therapeutic agents for FOP, and their induced ASP-RNAi may pave the way for the achievement of radical treatment of FOP and/or for the relief of its severe symptoms.

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“…At birth, only minor skeletal abnormalities occur in FOP patients, with congenital big toe malformation as the most characteristic feature. Most cases of FOP are caused by a c.617G.A point mutation in the ACVR1 gene, which encodes the ACVR1/ALK-2 type I receptor and confers a moderate gain-of-function in this BMP type I receptor (Shafritz et al 1996;de la Pena et al 2005;Fiori et al 2006;Shore et al 2006;Billings et al 2008;Fukuda et al 2009;Kaplan et al 2009;Shen et al 2009;Chaikuad et al 2012;Culbert et al 2014). Signaling through the ALK-2 receptor occurs in chondrocytes and osteoblasts, and is required for early stages of chondrogenesis (Culbert et al 2014).…”

Section: Heterotopic Ossification Caused By Dysregulation Of Bmp Signmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

Cited by 187 publications

References 43 publications

Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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