Endostatin inhibits endochondral ossification.
BACKGROUND
Angiogenesis is essential for the replacement of cartilage by bone during skeletal growth and regeneration. Vascular endothelial growth factor-A (VEGF-A) is a key regulator of angiogenesis whereas endostatin, a potent inhibitor of endothelial cell proliferation and migration, is a natural antagonist of VEGF-A. The regulatory role of these peptides in angiogenesis and bone formation was investigated using adenoviral gene delivery of VEGF-A and endostatin in a mouse ectopic ossification model.


METHODS
Bone formation was induced in the hamstring muscles of adult mice with native bone morphogenetic protein (BMP) extract implemented in gelatine gel together with VEGF-A and endostatin recombinant adenoviral vectors. The mice were sacrificed 1, 2, and 3 weeks after the operation and ectopic bone formation was followed radiographically and histologically.


RESULTS
Significant bone formation was induced by BMP extract in all treatment groups. VEGF-A stimulated and endostatin prevented the formation of FVIII-related antigen-positive vessels as well as the number of cartilage-resorbing chondroclasts/osteoclasts. Endostatin alone or in conjugation with VEGF-A reduced bone formation. Excess of VEGF-A stimulated and endostatin reduced bone formation, respectively, at the 3-week time point.


CONCLUSIONS
Our findings indicate that endostatin retards the cartilage phase in endochondral ossification which subsequently reduces bone formation in our experimental model. We conclude that bone growth and healing, which share features with ectopic bone formation, may be regulated by endostatin.
Sipola
A
A
Department of Anatomy and Cell Biology, University of Oulu, Finland.
Ilvesaro
J
J
Birr
E
E
Jalovaara
P
P
Pettersson
R F
RF
Stenbäck
F
F
Ylä-Herttuala
S
S
Hautala
T
T
Tuukkanen
J
J
D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D002356:Cartilage / Q000000981:diagnostic imaging / Q000187:drug effects*; D043169:Endostatins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011859:Radiography
D043169:Endostatins