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CK2
Ser 24
CK2
Ser 114
CK2
Ser 227
PKA
Asn 285
P
P
P
N
119
44
78
121 145
167
255
300
366 382
418
P
Phosphorylation
N
N-glycosylation
Heparin binding motif
Signal peptide
Antiangiogenic activity
Collagen binding motif
Reactive center loop
Neurotrophic activity
FIGURE 17.1
Schematic representation of protein structure of PEDF. PKA, protein kinase A; CK2, casein kinase 2; Ser, serine; Asn, aspara-
gine. This figure is reproduced in color in the color plate section.
notch signaling to regulate self-renewal of neuronal stem
cells; on the other hand, PEDF inhibited Wnt signaling
by binding to LRP6 in the eye.
The function of PEDF in bone has not been well
studied. PEDF is expressed in the major cell types in
bone such as chrondrocytes, osteoblasts and osteo-
clasts.
17,57-59
Akiyama et al. have demonstrated that
PEDF inhibits osteoclast formation and bone resorp-
tion activity by inducing osteoprotegerin production.
59
More recently, Bogan et al. have shown that PEDF-null
mice exhibited reduced trabecular bone volume and an
increase in unmineralized bone matrix.
60
Using
in vitro
studies, they also showed enhanced mineral deposi-
tion in osteoblasts from PEDF-null mice. Although
in vivo
mouse phenotypes are consistent with the skel-
etal pathology observed in human OI type VI patients,
the mechanisms by which PEDF regulates mineraliza-
tion remain unclear.
regulating bone mineralization and can have several
clinical implications. First, measurement of serum PEDF
can be used as a screening tool for diagnosis of OI type
VI. Second, PEDF replacement could be a potential ther-
apeutic strategy for OI type VI patients. Finally, further
understanding of PEDF or its downstream signaling in
bone could lead to development of therapies for other
bone diseases such as osteoporosis.
Despite the expression of PEDF in major bone
cells, the role of PEDF in bone homeostasis is not well
understood. Based on studies in other cell and tissue
types, there are several possible mechanisms by which
PEDF could regulate bone homeostasis. First, PEDF
could regulate bone matrix formation by binding to the
extracellular matrix, because it contains binding motifs
for collagen and glycosaminoglycans. Second, PEDF
may modulate intracellular signaling to regulate bone
homeostasis, because it is known to regulate several
intracellular signaling pathways in other cell types. For
example, recent findings showed that PEDF could mod-
ulate Notch and Wnt signaling which are important for
bone development and homeostasis. Finally, nuclear sig-
naling of PEDF may be a novel molecular mechanism
by which it regulates bone homeostasis and mineraliza-
tion. Further investigation of the role of PEDF in bone
by using mouse genetic models and molecular biology
will potentially open new avenues for the development
of clinical and therapeutic strategies for OI type VI.
CONCLUSION
OI type VI is a unique form of OI that is pathologi-
cally distinct from the other forms of OI as patients show
a mineralization defect in bone similar to osteomalacia.
Recently, several groups have identified that loss-of-func-
tion mutations in
SERPINF1
cause OI type VI.
SERPINF1
encodes PEDF which has been extensively studied as an
antiangiogenic, neurotrophic and neuroprotective fac-
tor. Complete loss of PEDF surprisingly results in bone
mineralization defects in humans. Interestingly, the
PEDF knockout mice also have similar bone phenotypes.
This genetic finding suggests a novel role for PEDF in
Acknowledgment
This work was supported in part by NRSA fellowship F32 AR063616
(KSJ) and Pediatric Endocrine Society Research Fellowship Award (MG).
