ACVR1
Activin receptor type-1 precursor (EC 2.7.11.30) (Activin receptor type I) (ACTR-I) (Activin receptor-like kinase 2) (ALK-2) (Serine/threonine-protein kinase receptor R1) (SKR1) (TGF-B superfamily receptor type I) (TSR-I) [ACVRLK2]
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Segmental progeroid syndromes are commonly represented by genetic conditions which recapitulate aspects of physiological aging by similar, disparate, or unknown mechanisms. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by mutations in the gene for ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor, and results in the formation of extra-skeletal ossification and a constellation of others features, many of which resemble accelerated aging. The median estimated lifespan of individuals with FOP is approximately 56 years of age. Characteristics of precocious aging in FOP include both those that are related to dysregulated BMP signaling as well as those secondary to early immobilization. Progeroid features that may primarily be associated with mutations in ACVR1 include osteoarthritis, hearing loss, alopecia, subcutaneous lipodystrophy, myelination defects, heightened inflammation, menstrual abnormalities, and perhaps nephrolithiasis. Progeroid features that may secondarily be related to immobilization from progressive heterotopic ossification include decreased vital capacity, osteoporosis, fractures, sarcopenia, and predisposition to respiratory infections. Some manifestations of precocious aging may be attributed to both primary and secondary effects of FOP. At the level of lesion formation in FOP, soft tissue injury resulting in hypoxia, cell damage, and inflammation may lead to the accumulation of senescent cells as in aged tissue. Production of Activin A, platelet-derived growth factor, metalloproteinases, interleukin 6, and other inflammatory cytokines as part of the senescence-associated secretory phenotype could conceivably mediate the initial signaling cascade that results in the intense fibroproliferative response as well as the tissue-resident stem cell reprogramming leading up to ectopic endochondral bone formation. Consideration of FOP as a segmental progeroid syndrome offers a unique perspective into potential mechanisms of normal aging and may also provide insight for identification of new targets for therapeutic interventions in FOP.
Keywords
- ACVR1
- activin A
- cell senescence
- fibrodysplasia ossificans progressiva
- progeroid syndrome
Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7). In normal fibroblasts, the efficiency of iPSC generation was enhanced by transducing mutant ACVR1 (617G > A) or SMAD1 or adding BMP4 protein at early times during the reprogramming. In contrast, adding BMP4 at later times decreased iPSC generation. ID genes, transcriptional targets of BMP-SMAD signaling, were critical for iPSC generation. The BMP-SMAD-ID signaling axis suppressed p16/INK4A-mediated cell senescence, a major barrier to reprogramming. These results using patient cells carrying the ACVR1 R206H mutation reveal how cellular signaling and gene expression change during the reprogramming processes.
MeSH Terms
- Activin Receptors, Type I
- Adolescent
- Adult
- Animals
- Bone Morphogenetic Proteins
- Cell Line
- Cellular Reprogramming
- Cellular Senescence
- Child
- Cyclin-Dependent Kinase Inhibitor p16
- Female
- Fibroblasts
- Humans
- Induced Pluripotent Stem Cells
- Male
- Mice, Transgenic
- Middle Aged
- Mutation
- Myositis Ossificans
- Signal Transduction
- Smad Proteins
Keywords
- BMP
- FOP
- pluripotency
- reprogramming
- senescence