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Bone Abstracts (2013) 1 W5.3 | DOI: 10.1530/boneabs.1.W5.3

ECTS2013 Workshops Anabolic bone therapies (3 abstracts)

Therapeutic targeting of activin signaling

Marco Eijken

Erasmus Medical Center, Rotterdam, The Netherland.

Recent studies have demonstrated that activin signalling plays a crucial role in the skeleton. Activins control both osteoblast and osteoclast function and are present in the bone extracellular matrix. This makes activin signalling an important new therapeutic target for a dual anabolic antiresorptive intervention in osteoporosis.

Activins belong to the large TGF-β superfamily that also includes BMPs, TGFβs and GDFs. Like other TGF-β members, activins elicit their biological responses by binding to type I and type II serine/threonine kinase receptors at the cell surface. Upon ligand binding, activin signalling is further transduced by phosphorylation of Smad2/3 intracellular signalling proteins.

In human osteoblast cultures activins strongly suppress in vitro bone formation in an auto/paracrine manner. Subsequent mechanistic studies in human osteoblasts demonstrated that activins elicit their inhibitory effect by altering the bone extra cellular matrix and by limiting the production of bone matrix vesicles.

Although also opposing effects have been reported using other cell models, the inhibitory effects of activins on bone are supported by studies in rodents and primates. In these studies neutralisation of activin signalling using activin type IIA decoy receptors strongly increased trabecular bone volume due to enhanced bone formation and decreased bone resorption.

At the tissue level activins are locally antagonised by follistatin and inhibins. Follistatin is an extracellular protein that besides activins also binds to and neutralises other TGF-β members including myostatin. Myostatin is well known for its inhibitory effect on muscle growth and myostatin neutralization has been shown to lead to enhanced muscle strength. Therefore a follistatin-based therapy might be an unique approach that offers the potential to reduce the risk for fractures in osteoporosis by increasing both bone and muscle strength.

Volume 1

European Calcified Tissue Society Congress 2013

Lisbon, Portugal
18 May 2013 - 22 May 2013

European Calcified Tissue Society 

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