Analysis of the TGF-b family ligands that are increased in regenerating skeletal muscle and induce BMP signaling via a mutant ALK2 associated with fibrodysplasia ossificans progressiva

Objectives: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification (HO) in soft tissues, such as skeletal muscle, tendons and ligaments, especially after trauma. A gain-of-function mutation in ALK2, ALK2(R206H), is commonly found in patients with typical FOP. ALK2 is a type I receptor of TGF-b family and transduces osteogenic signaling by phosphorylating Smad1 and Smad5. In the present study, we examined expression levels of each member of the TGF- b family in regenerating skeletal muscle and their biological activity on ALK2(R206H) in vitro.
Methods: Muscle injury was induced by injecting snake venoms into limb muscle of C57BL/6 mice.
Results: Multiple inflammatory cells were observed in the injured muscle tissues on day 3 after the injection. Quantitative RT-PCR analysis of the TGF-b family ligands revealed that more than 10 members were increased in the injured muscle. Among them, BMP-7, activinA and activinB induced BMP-specific luciferase reporter activities in C2C12 cells expressing human ALK2(R206H).
Conclusions: Some ligands of the TGF-b family increased during muscle regeneration contribute to the muscle trauma-induced HO in FOP.