A. Fibrodysplasia Ossificans Progressiva (FOP). In wild-type cells,
activin A antagonizes BMP signaling by forming an inhibitory, non-signaling
complex with ALK2 and type II receptors. In FOP, disease-causing ALK2 variants
perceive activin A as an agonist that aberrantly activates the SMAD1/5/8
pathway, and, thus, induces osteogenic differentiation of fibroadipogenic
progenitors to form ectopic bone. B. Wasting Syndrome/Cachexia. BMP signaling is
vital for muscle and adipose tissue formation and maintenance. Elevated
activin/GDF levels in patients with pancreatic cancers may antagonize
BMP-SMAD1/5/8 activity in these tissues, contributing to cancer cachexia. C.
Pulmonary Arterial Hypertension (PAH). Deficient BMP-SMAD1/5/8 and increased
activin-SMAD2/3 signaling may contribute to endothelial arterial cell
proliferation in PAH patients, and, thus, to the narrowing of pulmonary
arteries. Increased activin/GDF-11 levels could promote PAH by shifting the
balance from SMAD1/5/8 to SMAD2/3 signaling. D. Multiple Myeloma (MM). BMP
signaling helps maintain MM cells in a slow-proliferating state. Activin A
expression is induced in the bone marrow of MM patients and may contribute to
tumor cell expansion by antagonizing BMP activity. Also, activin A may alter
bone homeostasis and contribute to MM bone disease by suppressing osteoblastic
bone formation and inducing osteoclastic bone destruction.