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CHAPTER
22
Transforming Growth Factor Beta and
Bone: Lessons Learned from TGFbeta-
R
elated Condition
s
Bart Loeys
Antwerp University Hospital/University of Antwerp, Antwerp, Belgium
INTRODUCTION
NORMAL TGFBETA SIGNALING
CASCADE
Over the last decade an intimate interplay between
the extracellular matrix and the transforming growth
factor beta (TGFbeta) signaling pathway has been
revealed through the study of different monogenic
conditions. The extracellular matrix is composed of a
fibrillar component with structural molecules such as
collagen, fibrillin and elastin and an amorphous com-
ponent with glycoproteins and proteoglycans. Through
the study of human monogenic conditions and relevant
mouse models, it has become increasingly clear that the
fibrillar molecules, in addition to their structural role,
also have an important role in regulating the function
of cytokines such as transforming growth factor beta.
Transforming growth factor beta belongs to a super-
family of signaling proteins that are involved in several
biological processes including cell growth and migra-
tion, differentiation and apoptosis, but also extracellu-
lar matrix production and homeostasis. This TGFbeta
superfamily consists of 33 secreted cytokines in human,
which include TGFbeta, bone morphogenetic proteins
(BMPs) and growth and differentiation factors (GDFs),
activins/inhibins and nodal-related proteins.
1
Although
many of the lessons learned so far are derived from the
study of the cardiovascular system, the first clues in the
skeletal system have also emerged.
2,3
In this chapter we
will first discuss normal TGFbeta signaling and subse-
quently review the human monogenic conditions with
tall and short stature, respectively, that have relevance
to the role of TGFbeta in bone.
The TGFbeta family is composed of three cytokines,
respectively TGFbeta 1, 2 and 3. TGFbeta is secreted
from the cell in the context of a large latent complex
(LLC) composed of a disulfide-bonded homodimer of
mature TGFbeta associated non-covalently with latency-
associated proteins (LAPs; homodimers of the N-terminal
fragment of precursor TGFbeta) and a covalently attached
molecule of latent TGFbeta binding protein (LTBP). Four
different LTBPs have been described and the structure of
LTBP is closely related to the structure of fibrillin-1. This
resemblance facilitates interaction and, for example, the
C-terminus of LTBP1 binds to the N-terminal part of fibril-
lin-1.
4
In addition, LTBPs interact with other extracellu-
lar matrix proteins such as fibronectin and as such allow
the LLC to bind to the matrix. The LLC keeps the cyto-
kine in an inactive state and for activation of the TGFbeta
the LLC must be released from the matrix. Subsequently,
both the LAPs and the LTBPs have to be removed or at
least modulation of their interaction is essential for any of
the TGFbeta isoforms to function.
Once active TGFbeta is released from the extracellu-
lar matrix, binding to the TGFbeta receptors at the cell
surface occurs. Upon binding of the ligand, a hetero-
tetrameric complex of two types of transmembrane ser-
ine/threonine kinase receptors, designated as the type
I and type II receptors, is formed. Ligand receptor com-
plex formation leads to activation of the type I receptor
through type II receptor-mediated phosphorylation of
