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synthesis and processing have recently been linked to
OI (
Figure 5.4
). A mutation in a key transcription fac-
tor directing osteoblast differentiation, Osterix (
OSX
or
SP7
), was associated with OI.
82
Finally, mutations in the
SERPINF1
gene that encodes pigment epithelium-derived
factor (PEDF) was also linked to recessive OI.
83
PEDF
both upregulates osteoprotegerin, which inhibits osteo-
clast maturation, and induces differentiation of precur-
sor cells into mature osteoblasts.
84
Thus PEDF mutations
may also be impacting osteoblast lineage differentiation.
In SERPINF1 mutants, post-translational modification
and secretion of type I collagen were reported to be nor-
mal.
83
The status of collagen post-translational modifica-
tions in the proband with a mutation in
SP7
has not been
determined.
In Vitro
Effects on Collagen
Because of the relative ease of obtaining fibroblasts
from probands by punch biopsy and subsequent tissue
culture explant expansion of the cells, fibroblasts have
been used to investigate the molecular correlates of the
OI phenotype. In fibroblasts derived from donors with
OI, the secretion rate and total amount of type I procol-
lagen was typically found to be reduced compared to
that of cells derived from normal donors.
89-98
Reduced
collagen content was found irrespective of Sillence clas-
sification type and the presence or absence of structural
abnormalities in type I collagen. Molecular defects in
protein coding as well as messenger RNA synthesis,
stability and processing were identified.57,99-102
57,99-102
The col-
lagen produced by OI cells often exhibited a reduced
stability as reflected by a decreased thermal denaturation
temperature.
103-105
OI cell collagen was often overmodi-
ied.
106-108
Selective deposition with preferential deg-
radation of structurally abnormal type I collagen such
that mostly structurally normal collagen heterotrimers
were incorporated in the matrix has been found.
109-111
In
detailed studies of collagen metabolism, no correlation
between biochemical parameters (thermal stability, kinet-
ics of procollagen secretion and rate of maturation from
procollagen to collagen) and clinical phenotype were
consistently observed.
112
CONSEQUENCES
Skin and Fibroblasts in OI
Skin manifestations of OI include thinning of the der-
mal layers and diffuse and unstructured collagen pack-
ing in severe OI.
85,86
The skin of patients with OI is stiffer
and less elastic than normal skin.
87
The skin phenotype
in OI is reminiscent of physiological changes in skin
associated with increasing age where decreased colla-
gen production with an increase in collagen crosslinking
gives rise to skin with reduced collagen content per unit
area of the skin, reduced resiliency and increased sag-
ging and wrinkling of the skin.
88
In Vitro
Effects in Other Molecular and Cellular
Domains
The proteoglycan levels produced by fibroblasts
derived from subjects with OI were distinct from those
Mesenchymal stem cell
Precursor
Pre-osteoblast
SP7/OSX
OPG
Osteoblast
Pre-osteoclast
PEDF
Osteoclast
Osteocyte
FIGURE 5.4
Osteoblast differentiation-related proteins mutated in OI. Mutations traceable to pigment epithelium-derived factor (PEDF) and
Osterix (OSX or SP7) have been implicated in additional autosomal recessive forms of OI. The dysregulation common to these mutations may involve
altered recruitment, differentiation and crosstalk between osteoblasts and osteoclasts.
