The focus of this project will be to investigate the role of the myostatin/GDF-11/activin branch of the
transforming growth factor-ß (TGF-ß) superfamily of secreted signaling molecules in regulating bone mass and
density. The important role that this signaling pathway plays in regulating bone homeostasis has been
documented by both pharmacologic and genetic studies targeting receptors for this group of ligands. Work
from several groups, including ours, has shown that systemic administration of soluble forms of either of the
activin type 2 receptors, ACVR2 and ACVR2B, is capable of inducing significant increases in bone density. By
genetically targeting these receptors in osteoblasts, we showed that at least part of this effect is due to
inhibition of direct signaling to bone. Strikingly, however, we very recently showed that targeting the type 1
receptors, ALK4 and ALK5, in osteoblasts led to much more substantial effects, resulting in increases in bone
mass and density by approximately 10-fold. These findings revealed the extraordinary capacity for bone
accrual that is normally kept in check by this regulatory system and suggest that the potential for increasing
bone mass and density by targeting this signaling pathway is substantially greater than previously appreciated.
As a starting point for developing the most effective strategies to harness the potential of targeting this pathway
for bone applications, we will elucidate the extracellular components that play key roles in this regulatory
network in bone. In Specific Aim 1, we will examine the roles of known inhibitory binding proteins for this group
of ligands in regulating bone structure. In our recent study, we carried out an extensive analysis of the role of
one binding protein, namely follistatin (FST), using genetically-targeted mouse lines in which expression levels
of FST were either up- or down-regulated. Here, we will examine the roles of the three other known binding
proteins, FSTL-3, GASP-1, and GASP-2, utilizing targeted mouse lines that we have generated carrying both
deletion and floxed alleles for each of these components. In Specific Aim 2, we will examine the roles of
specific ligands in this subgroup of the TGF-ß superfamily in regulating bone structure. In our recent study, we
showed that targeting two ligands simultaneously, namely myostatin and activin A, led to substantial increases
in bone mass and density but that these increases were significantly less pronounced than the approximately
10-fold effects that we observed upon targeting their type 1 receptors. Here, we will use genetic approaches to
examine the roles of a wider spectrum of ligands in this subgroup of the TGF-ß superfamily in regulating bone
structure. The overall goal of this project will be to elucidate the specific extracellular signaling components
that play key roles in regulating bone homeostasis with the long-term goal of developing the most effective
strategies to target this signaling pathway to treat bone loss.
