In vitro and in vivo endochondral bone formation models allow identification of anti-angiogenic compounds.
A major obstacle in the study of angiogenesis and the testing of new agents with anti-angiogenic potential has been the lack of experimental models with predictive in vivo value. We describe here the combined use of in vitro and in vivo angiogenesis models that are based on endochondral bone development. This approach led to the identification of a new inhibitor of matrix metalloprotease (MMP) activity that inhibits neovascularization in vitro and in vivo while osteoclast invasion, which occurs simultaneously during bone development, remained unaffected. In contrast, the broad-spectrum MMP-inhibitor marimastat inhibited both in vitro angiogenesis and osteoclastogenesis dose-dependently but displayed severe toxic side effects in vivo. The combined use of these experimental models may, therefore, facilitate the discovery of mechanisms underlying angiogenesis and lead to identification of new pharmacological compounds with clinical efficacy and appropriate selectivity in the treatment of angiogenesis-dependent disorders like arthritis and cancer.
van der Pluijm
Gabri
G
Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands. g.van_der_pluijm@lumc.nl
Deckers
Martine
M
Sijmons
Bianca
B
de Groot
Henny
H
Bird
John
J
Wills
Ruth
R
Papapoulos
Socrates
S
Baxter
Andy
A
Löwik
Clemens
C
D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D001846:Bone Development / Q000502:physiology*; D001862:Bone Resorption / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008682:Metatarsal Bones / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C100342:marimastat; D020782:Matrix Metalloproteinases