期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：33
DOI：10.1073/pnas.2111401118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Maintenance of skeletal muscle and bone is regulated by key signaling proteins belonging to the transforming growth factor family. Here, we present genetic studies in mice showing that follistatin, which normally blocks the activities of these proteins, acts locally in an exquisitely dose-dependent manner to control muscle and bone growth. Moreover, our studies targeting the receptors for these proteins reveal the enormous capacity for bone growth that is normally kept in check by this signaling system. These findings have implications for strategies to target this signaling pathway for clinical applications to treat patients with muscle and bone loss.
Skeletal muscle and bone homeostasis are regulated by members of the myostatin/GDF-11/activin branch of the transforming growth factor-β superfamily, which share many regulatory components, including inhibitory extracellular binding proteins and receptors that mediate signaling. Here, we present the results of genetic studies demonstrating a critical role for the binding protein follistatin (FST) in regulating both skeletal muscle and bone. Using an allelic series corresponding to varying expression levels of endogenous
Fst, we show that FST acts in an exquisitely dose-dependent manner to regulate both muscle mass and bone density. Moreover, by employing a genetic strategy to target
Fst expression only in the posterior (caudal) region of the animal, we show that the effects of
Fst loss are mostly restricted to the posterior region, implying that locally produced FST plays a much more important role than circulating FST with respect to regulation of muscle and bone. Finally, we show that targeting receptors for these ligands specifically in osteoblasts leads to dramatic increases in bone mass, with trabecular bone volume fraction being increased by 12- to 13-fold and bone mineral density being increased by 8- to 9-fold in humeri, femurs, and lumbar vertebrae. These findings demonstrate that bone, like muscle, has an enormous inherent capacity for growth that is normally kept in check by this signaling system and suggest that the extent to which this regulatory mechanism may be used throughout the body to regulate tissue mass may be more significant than previously appreciated.
关键词：enfollistatin;myostatin;activin;bone mineral density;chalone
