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translation of this allele, e.g., due to RNA degradation). 1
Yet, these mutations should also disrupt the balance
between the pro-α1(I) and pro-α2(I) chains in the ER.
Excess pro-α2(I) chains are transported through Golgi to
lysosomes for degradation, 106 but intracellular accumu-
lation of these chains and the increased need for their
degradation might affect osteoblast differentiation and
function.
Disruption of osteoblast differentiation and function
by procollagen misfolding and retention in the ER was
documented in the Aga2 mouse with a C-propeptide
mutation 95 and Brtl mouse with a Gly substitution in
the α1(I) chain. 122,123 In the Aga2 mouse, one might
expect osteoblast malfunction to be the primary cause of
pathology since most of the mutant molecules appear to
be retained and degraded by cells. 95 Yet, even inefficient
secretion of these mutant molecules could affect fiber
formation and function by altering collagen interactions,
because such molecules are likely to be overmodified
and their defective C-propeptides might not be prop-
erly cleaved. In the Brtl mouse, the triple-helix muta-
tion might be expected to affect collagen interactions,
but measurements of collagen-collagen interactions in
tendons and in vitro fibrillogenesis experiments reveal
no such effects. 124 Instead, studies of collagen-producing
cells point to osteoblast malfunction as a potential main
contributing factor. 89,122,123 Normalization of the bone
structure and properties by 1-2% engraftment of trans-
planted wild-type cells further support this hypothe-
sis. 125 The donor cells produce ~10 times more collagen
than their fraction of total osteoblast population, empha-
sizing rather dramatic malfunction of host osteoblasts.
Based on these and other observations, disruption of
osteoblast differentiation and function seems to be an
important factor in most OI cases caused by mutations
that affect procollagen folding. 80
Disruptions in collagen fiber formation, structure and
function by uncleaved propeptides were reported for
several mutations in the triple helix as well as for muta-
tions within propeptide cleavage sites and enzymes, but
not all of these disruptions were found to contribute sig-
nificantly to bone pathology. In particular, incorporation
of molecules with uncleaved N-propeptides into collagen
fibers alters the fiber size, structure and strength. 126-129
Mutations in the N-propeptide cleavage site and in
the N-proteinase that cleaves at this site lead to Ehlers-
Danlos syndrome (EDS) type VII with severe joint
hyperextensibility and skin fragility, but only mild or
no manifestations of bone pathology. 127,130-132 Mutations
in the N-anchor region of the triple helix cause EDS VII-
like joint hyperextensibility in combination with moder-
ately severe OI. 133 Apparently, disruption of procollagen
folding and osteoblast function by N-anchor mutations
produces OI symptoms and disruption of N-propeptide
cleavage produces EDS symptoms. 103,133 Mutations in
the C-propeptide cleavage site and the corresponding
C-proteinase (BMP1) alter collagen-mineral interactions
and cause OI with higher than expected bone mineral
density. 15,134,135 Collagen fiber mineralization in these
patients is likely disrupted by incorporation of molecules
with uncleaved C-propeptides. 135
Abnormal collagen-collagen interactions were docu-
mented for PLOD2 13,136 and FKBP10 85 mutations, which
produced overlapping OI phenotypes 11-14,137 and similar
deficiency in collagen telopeptide lysyl hydroxylation 85
by lysyl hydroxylase 2 (LH2) encoded by PLOD2 . The
telopeptide lysyl hydroxylation deficiency prevents
covalent crosslinking between adjacent molecules in col-
lagen fibers.138 138 Dysregulated collagen fiber deposition
in cultures of dermal fibroblasts from OI patients with
FKBP10 mutations also appears to be a consequence
of the deficient crosslinking. 85 Yet, FKBP65 encoded by
FKBP10 is an ER chaperone 83,139 and stress-response pro-
tein involved in Ca 2+ signaling, 140 so that FKBP10 muta-
tions might cause abnormal collagen biosynthesis and /
or malfunction of osteoblasts as well. PLOD2 mutations
might do the same by altering FKBP65 functions, since
abnormal lysyl hydroxylation in FKBP65-deficient cells
points to an interaction between FKBP65 and LH2. 85
Aberrant regulation of collagen fibrillogenesis by
extracellular matrix molecules might underlie OI caused
by SERPINF1 mutations. Pigment epithelium derived
factor (PEDF) encoded by SERPINF1 is a secreted col-
lagen-binding protein 141 that does not seem to affect
collagen biosynthesis 16 but is a potent fibrillogenesis
inhibitor. 142 It is capable of significantly slowing down
fiber formation at physiological concentrations by bind-
ing to the triple helix and blocking collagen-collagen
interactions (Konopko et  al., unpublished results), so
that it might be an important negative fibrillogenesis
regulator in vivo . PEDF might affect bone formation and
quality, e.g., by preventing excessive deposition of dis-
organized collagen fibers, which would explain why
PEDF deficiency causes OI in humans 16,17,143 but not in
mice. 144,145 (Collagen fibers are less well organized and
their formation might be less tightly regulated in mouse
bones; and fibrillogenesis of mouse collagen occurs
under much more permissive conditions compared to
human collagen.) The delayed onset of bone pathology
in type VI OI patients 146 caused by PEDF deficiency17 17
might also be explained by runaway fibrillogenesis,
which is likely to be more detrimental for the deposition
of better organized lamellar bone during remodeling
than for the deposition of woven bone in early develop-
ment. Yet, PEDF has been reported to affect the function
of osteoblasts and osteoclasts too. 147,148
One of the most complex scenarios for the analysis of
different contributions to bone matrix dysregulation in
OI is exemplified by CRTAP , LEPRE1 and PPIB muta-
tions. Prolyl-3-hydroxylase 1 (P3H1) encoded by LEPRE1
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