Novel and selective small molecule stimulators of osteoprotegerin expression inhibit bone resorption.
Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor superfamily, is a potent inhibitor of osteoclast formation and bone resorption. Because OPG functions physiologically as a locally generated (paracrine) factor, we used high-throughput screening to identify small molecules that enhance the activity of the promoter of the human OPG gene. We found three structurally unrelated compounds that selectively increased OPG gene transcription, OPG mRNA levels, and OPG protein production and release by osteoblastic cells. Structural analysis of one compound, a benzamide derivative, led to the identification of four related molecules, which are also OPG inducers. The most potent of these compounds, Cmpd 5 inhibited osteoclast formation and parathyroid hormone-induced calvarial bone resorption. In vivo, Cmpd 5 completely blocked resorptive activity (serum calcium, osteoclast number) in parathyroid hormone-treated rats. Furthermore, Cmpd 5 reduced the ability of a rat breast cancer to metastasize to bone. Finally, the compound also prevented bone loss in a rat adjuvant arthritis model. These results provide proof of the concept that low molecular weight compounds can enhance OPG production in ways that can result in effective therapies.
Onyia
Jude E
JE
Gene Regulation, Bone and Enabling Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Galvin
Rachelle J Sells
RJ
Ma
Yanfei L
YL
Halladay
David L
DL
Miles
Rebecca R
RR
Yang
Xuhao
X
Fuson
Tina
T
Cain
Ricky L
RL
Zeng
Qing Qiang
QQ
Chandrasekhar
S
S
Emkey
Renee
R
Xu
Yanping
Y
Thirunavukkarasu
Kannan
K
Bryant
Henry U
HU
Martin
T John
TJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001862:Bone Resorption / Q000188:drug therapy*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects; D053244:Osteoprotegerin; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D001549:Benzamides; D006023:Glycoproteins; D053244:Osteoprotegerin; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; C506032:Tnfrsf11b protein, rat