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Pregnancy-associated plasma protein-A increases osteoblast proliferation in vitro and bone formation in vivo.
- Qin X, Wergedal JE, Rehage M, Tran K, Newton J, Lam P, Baylink DJ, Mohan S
Endocrinology. 2006 Dec;147(12):5653-61. Epub 2006 Aug 31.
Pregnancy-associated plasma protein
(PAPP)-A, a protease
for IGF
binding
protein
(IGFBP)-2, -4, and -5, may enhance IGF
action by increasing its bioavailability.
Here we have determined the role
and mechanism
of action of PAPP-A in the regulation
of osteoblast
proliferation
in vitro
and bone metabolism
in vivo.
Recombinant
PAPP-A (100 ng/ml)
significantly increased osteoblast
proliferation
and free IGF-I concentration. These effects were abolished by noncleavable IGFBP-4, suggesting that PAPP-A promotes osteoblast
proliferation
by increasing IGF
bioavailability.
To determine whether PAPP-A exerts an anabolic
effect on bone in vivo,
we developed transgenic mice
that overexpress PAPP-A in osteoblasts
using the 2.3-kb rat type I collagen
promoter.
Consistent with the increase in IGFBP-4 proteolysis,
free IGF-I concentration was significantly increased in the conditioned medium
of cultured
osteoblasts
derived from transgenic mice
compared with the wild-type littermates. Calvarial bone thickness, bone marrow
cavity, and skull bone mineral density were significantly increased in transgenic mice.
Bone size-related parameters in femur
and tibia
such as total bone area and periosteal
circumference as determined by peripheral
quantitated computed tomography
and histological
analysis
were significantly increased in transgenic mice.
Bone formation rate and osteoid
surface were increased by more than 2-fold, whereas bone resorbing surface was unaffected. These anabolic
effects were sustained with aging.
These findings provide strong evidence that PAPP-A acts as a potent anabolic
factor
in the regulation
of bone formation. Thus, enhancing IGF
bioavailability
by PAPP-A can be a powerful strategy
in the treatment of certain metabolic
diseases such as osteoporosis.
This abstract at PubMed.