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Published on: October 6, 2023
Interplay between ALK2R206H mutant receptor and autophagy signaling regulates receptor stability and its chondrogenic
Laura Coculo1,2, Marius Wits3, Irene Mariani1,2
1Institute of Molecular Biology and Pathology, National Research Council (CNR), Rome, Italy.
Abstract:
Heterozygous mutations in the Bone morphogenetic protein (BMP) type I receptor ACVR1, encoding activin-like kinase 2 (ALK2), underlie all cases of the rare genetic musculoskeletal disorder Fibrodysplasia Ossificans Progressiva (FOP). The most commonly found mutant ALK2 p.R206H receptor variant exhibits loss of auto inhibition of BMP signaling and can be activated by Activins, while wild-type receptors remain unresponsive. Consequently, the downstream chondrogenic signaling is enhanced, thus driving heterotopic ossification within soft connective tissues. Despite several investigational treatments being evaluated in clinical trials, no cure for FOP exists today. The cellular and molecular mechanisms underlying disease progression are still being deciphered. In this study, we show a close interplay between the mutant ALK2R206H receptor signaling and dysregulation of the autophagic flux triggered by hypoxia. Mechanistically, reduced autophagic flux correlates with increased stability of ALK2R206H, resulting in sustained signaling. Of note, we demonstrated that Rapamycin, under clinical investigation as a treatment for FOP, inhibits chondrogenic differentiation in an autophagy-dependent manner. Consistently, other pharmacological autophagy inducers, like Spermidine, can reduce ALK2R206H driven chondrogenic differentiation in vitro. These results were verified in FOP patient-derived cells. In conclusion, this study shows that aberrant autophagic flux mediates sustained ALK2R206H signaling, introducing a novel druggable target in FOP by reactivating autophagy.
Insights
Fibrodysplasia Ossificans Progressiva (FOP) involves mutant ALK2 receptor signaling. This study reveals that impaired autophagy flux stabilizes mutant ALK2, driving disease progression, and suggests autophagy reactivation as a therapeutic strategy.
Area of Science:
- Genetics and Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by heterozygous mutations in the ACVR1 gene, encoding the Bone morphogenetic protein (BMP) type I receptor ALK2 (activin-like kinase 2).
- The common ALK2 p.R206H mutation leads to constitutive BMP signaling, promoting heterotopic ossification, but underlying disease mechanisms require further elucidation.
- Current treatments for FOP are limited, highlighting the need for novel therapeutic targets and a deeper understanding of disease pathogenesis.
Purpose of the Study:
- To investigate the interplay between mutant ALK2 signaling and autophagic flux in Fibrodysplasia Ossificans Progressiva (FOP).
- To identify cellular mechanisms contributing to sustained mutant ALK2 activity and chondrogenic differentiation in FOP.
- To evaluate the therapeutic potential of modulating autophagy for FOP treatment.
Main Methods:
- Utilized patient-derived cells and in vitro models to study mutant ALK2 (activin-like kinase 2) signaling pathways.
- Investigated the role of hypoxia in modulating autophagic flux and its impact on ALK2 stability.
- Assessed the effects of pharmacological autophagy modulators, including Rapamycin and Spermidine, on chondrogenic differentiation.
Main Results:
- Demonstrated a correlation between reduced autophagic flux and increased stability of the mutant ALK2R206H receptor, leading to sustained downstream signaling.
- Showed that Rapamycin, an investigational FOP treatment, inhibits chondrogenic differentiation via an autophagy-dependent mechanism.
- Confirmed that autophagy inducers like Spermidine can suppress mutant ALK2-driven chondrogenic differentiation in vitro and in patient-derived cells.
Conclusions:
- Aberrant autophagic flux is a key mediator of sustained mutant ALK2 signaling in Fibrodysplasia Ossificans Progressiva (FOP).
- Reactivating autophagy presents a promising, novel therapeutic strategy for FOP.
- Targeting the autophagic pathway offers a new avenue for drug development in FOP treatment.
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