what-when-how
In Depth Tutorials and Information
serine and threonine residues. TGFbeta interacts with the
TGFbeta receptor 2 (TGFBR2), which activates TGFbeta
receptor 1 (also known as ALK5) through its phosphory-
lation. For other members of the TGFbeta superfamily
other type I and II receptors are used. Subsequently, the
activated TGFBR1 phosphorylates the rSMADs or recep-
tor-regulated SMADs, SMAD2 and SMAD3. Similarly,
BMPs (bone morphogenetic proteins) activate SMADs1,
5 and 8. The active phosphorylated SMAD2 or 3 then
interacts with SMAD4 (co-mediator SMAD), translocates
to the nucleus and modulates gene expression. This pro-
cess is also regulated by the inhibitory SMADs (SMAD6
and 7) and other regulatory proteins such as SKI and
SKIL (Sloan-Kettering Institute and SKI-like oncogene).
In addition to this regulation, the TGFbeta signaling
pathways are further fine-tuned at multiple levels, such
as by the presence of extracellular antagonists that mod-
ify ligand activity and the availability of co-receptors that
modulate affinity of the ligand for its receptors.
5
Tissue
specificity is also achieved by spatio-temporal expression
of these modulatory proteins.
and inflammation, analogous to traditional destruc-
tive emphysema. Instead, diffuse widening of the distal
airspace at birth due to failure of septation of the preal-
veolar saccule, with no associated destructive or inflam-
matory changes, was observed.
8
It was hypothesized that
perhaps this related to altered regulation of and signal-
ing by the TGFbeta family of cytokines. In keeping with
this hypothesis, increased free TGFbeta in the fibrillin-1-
deficient lung in association with reduced LAP (sug-
gesting excessive activation rather than production of
TGFbeta) and increased activity of a transgenic TGFbeta
reporter allele were shown. Finally, systemic adminis-
tration of TGFbeta-neutralizing antibody rescued lung
septation in mouse models of MFS, providing evidence
for a cause-and-effect relationship. Subsequent experi-
ments showed that the same process underlies other
phenotypic manifestations of MFS, such as myxomatous
changes of the AV valves,
9
poor muscle regeneration
capacity
10
and aortic elastic fiber fragmentation.
11
The Loeys-Dietz syndrome (LDS) was first described
in 2005 as an aortic aneurysm syndrome with prominent
craniofacial, skeletal and cutaneous findings.12,13
12,13
A clini-
cal triad of hypertelorism, cleft palate/bifid uvula and
aortic/arterial aneurysm with generalized arterial tor-
tuosity is the most overt presentation. After the initial
discovery, a wide variability in clinical phenotype has
been observed, including Marfan-like,
14
vascular Ehlers-
Danlos (EDS)-like and isolated familial thoracic aortic
aneurysm (iFTAA)-like presentations.
15
LDS is caused
by mutations in the genes encoding either subunit of the
transforming growth factor-beta receptor (
TGFBR1/2
),
with
TGFBR2
mutations twice as common as
TGFBR1
.
Importantly, it was also shown that despite a loss-of-
function character of the
TGFBR1/2
mutations in LDS, the
overall effect on the pathway was an increase in TGFbeta
signaling through both canonical and non-canonical path-
ways (H. Dietz, personal communication).
With regards to the skeletal features, the overgrowth
in MFS is believed to be the consequence of inappropri-
ate linear growth of the long bones, leading to dispro-
portionate tall stature with increased armspan-to-height
ratio and decreased upper-to-lower segment ratios.
Overgrowth of the ribs leads to pectus deformities, with
pectus excavatum being the most common form but pec-
tus carinatum being the more specific finding for Marfan
syndrome. The positive wrist and thumb sign, exempli-
fying arachnodactyly, are the consequence of overgrowth
of the ingers and toes. Other recurrent skeletal findings
in patients with MFS include scoliosis, thoracolumbar
kyphosis, hindfoot deformity with pes planus, and pro-
trusio acetabuli. Reduced bone mineral density (BMD) is
sporadically reported in patients with Marfan syndrome,
but it is unclear if this increases the risk for bone frac-
ture in Marfan patients. The interpretation of the results
TGFBETA IN SYNDROMES WITH
TALL STATURE AND/OR LONG BONE
OVERGROWTH
Marfan syndrome (MFS) is a systemic disorder of
connective tissue caused by heterozygous mutations
in the gene (
FBN1
) encoding the extracellular matrix
protein fibrillin-1.6
6
Manifestations occur in many body
systems including the eye (lens dislocation, early and
severe myopia, retinal detachment), the skeleton (bone
overgrowth, joint laxity, pectus deformity, scoliosis), the
skin and integument (striae distensiae, recurrent her-
nia, dural ectasia), the lung (pneumothorax, chronic
obstructive pulmonary disease) and, most importantly,
the heart and blood vessels (aortic root aneurysm and
dissection, myxomatous changes of the AV valves, con-
gestive heart failure).
7
Fibrillin-1 monomers aggregate
to form complex extracellular structures called microfi-
brils that cluster at the margins of maturing elastic fibers
during embryogenesis. Early pathogenetic models for
MFS focused upon structural weakness of the tissues
imposed by microfibrillar deficiency and a postulated
consequent failure of elastogenesis. Subsequent studies
using genetically-defined animal models of MFS demon-
strated that fibrillin-1 is not needed for elastogenesis, as
previously inferred, but rather is critical for elastic fiber
maintenance in postnatal life. A breakthrough in the
understanding of the pathogenesis of MFS came while
studying lung disease in mouse models.
8
The expec-
tation was that the mice would show normal lungs
at birth, with gradual evidence of tissue destruction
