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In contrast, domain-specific missense mutations in
domain TB4 of FBN1 result in a rare condition called
stiff skin syndrome (SSS), a congenital form of scleroder-
mia.
32
All affected SSS patients lacked the skeletal, ocular
and cardiovascular findings of MFS, but presented with
congenital thickened skin and relatively short stature.
All patients had a missense mutation in
FBN1
, either
substituting or creating a cysteine residue in the fourth
TGFbeta binding protein-like motif of fibrillin-1, encoded
by exons 37 and 38. These cysteines are essential for the
proper folding of this motif and the unique feature of
this motif of fibrillin-1 is that it is the only domain that
encodes an RGD (Arg-Gly-Asp) sequence. This sequence
is known to mediate cell-matrix interactions via integrin
binding. The underlying pathogenic mechanism hypoth-
esized a loss of longitudinal growth and increased lateral
growth of microfibrils and a role for increased TGFbeta
signaling was also suggested. Both events are plausibly
explained by integrin-mediated cell-matrix attachments.
Informatively, specific
SMAD4
point mutations
were identified as the cause of Myhre syndrome, a
condition with short stature and a body habitus that is
reminiscent of stiff skin syndrome. Myhre syndrome
is characterized by pre- and postnatal short stature,
brachydactyly, facial dysmorphism (short palpebral is-
sures, maxillary hypoplasia, prognathism, short phil-
trum), thick skin, generalized muscle hypertrophy and
restricted joint mobility.
33
The skeletal manifestations
include thickened calvarium, cone-shaped epiphyses,
shortened tubular bones, hypoplastic iliac wings, broad
ribs and large vertebrae with short and large pedicles.
Other consistent findings are deafness of mixed con-
ductive and sensory type, developmental delay with
intellectual disability and/or behavioral disturbance,
cardiac defects and cryptorchidism. The
SMAD4
muta-
tion affected a specific amino acid isoleucine at posi-
tion 500. It was predicted that the mutant
SMAD4
protein would show increased stability, maybe due to
decreased ubiquitination, and as such an increase in
TGFbeta and BMP signaling was observed.
33
Increased TGFbeta signaling has also been shown in
another skeletal dysplasia characterized by increased
bone density, called osteopoikilosis. Osteopoikilosis
(and its related disorder, the Buschke-Ollendorf syn-
drome) is caused by heterozygous loss-of-function
mutations in the
LEMD3
gene. This gene codes for a
structural nuclear membrane protein that antagonizes
BMP and TGFbeta signaling.
34
from the above descriptions of genes and conditions it
is clear that TGFbeta signaling is important in skeletal
growth. An emerging body of evidence demonstrates
that extracellular microfibrils are intimately involved in
bone homeostasis by providing the structural scaffold
that modulates local TGFbeta and BMP bioavailability.
The precise mechanisms are not yet completely under-
stood but some lessons can already be deduced.
Fibrillin-1 and 2 are expressed in the developing and
mature limbs in a spatial and temporal-specific man-
ner.
35
Initially, fibrillins are mainly expressed in the
extracellular matrix of the emerging limb buds but later
in development fibrillins are expressed more widely
and found significantly in the perichondrium, growth
plate, bone and marrow stroma.
The first evidence for the role of regulation of BMP
signaling by fibrillins was derived from the study of
fibrillin-2 null mice.
36
Combined haploinsufficiency for
fibrillin-2 and BMP7 (but not mice haploinsufficient for
either) exhibit the same patterning defects with syn-
dactyly.
In vitro
studies of primary osteoblasts from
fibrillin-2 (but not fibrillin-1) null mice show impaired
osteoblast maturation due to increased latent TGFbeta
activation and signaling, which interferes with osterix-
stimulated production of collagen type I. By contrast,
the negative impact of increased TGFbeta activity in
Fbn1 null osteoblasts is apparently counteracted by
enhanced BMP signaling. Fibrillins seem to regulate
bone formation and homeostasis by balancing the local
release of TGFbeta and BMP molecules and by restrict-
ing TGFbeta bioavailability during osteogenesis.
37
In a
more recent study, it was also shown that both fibrillins
act as negative regulators of bone resorption, a TGFbeta-
mediated effect exerted through the RANKL pathway.
38
This delicate, time-dependent balance between bone
anabolism and catabolism probably offers an explana-
tion for the opposite observations of increased bone den-
sity in Camurati-Engelman and decreased bone density
in MFS/LDS, all conditions associated with TGFbeta
signaling dysregulation (
Figure 22.1
and
Table 22.1
).
Despite these interesting observations, many ques-
tions remain about the precise role of TGFbeta and BMP
signaling. For example, how can enhanced TGFbeta
signaling lead to both syndromes characterized by long
bone overgrowth and syndromes with short stature?
Probably, different spatial and time-dependent
effects on osteogenic differentiation underlie these
marked opposing phenotypes. The further elucidation
of the downstream pathways will help to unravel this
apparent paradox. Similarly, the contribution of the
ADAMTS proteins and other regulators of TGFbeta and
BMP signaling awaits further research. Ultimately, this
knowledge will be important for the understanding of
the role TGFbeta and BMP in the wide range of osteo-
genesis imperfecta phenotypes.
ROLE OF EXTRACELLULAR MATRIX
AND T
GFBETA IN SKELETAL GR
OWTH
Historically, there has been strong focus on the struc-
tural role of fibrillins, microfibrils and elastic fibers but
