Future anti-catabolic therapeutic targets in bone disease.
Understanding of the regulation of bone catabolism has advanced significantly over the past two decades with the identification of key enzymes that regulate osteoclast formation, activation, and survival following their knockout in mice or recognition of mutations in humans. This led to the discovery of specific inhibitors of some of these key enzymes as proof-of-concept lead compounds or potential clinical candidates for the prevention of osteoporosis and other diseases associated with increased bone resorption. Bisphosphonates have been the major therapeutic agents prescribed for the prevention of bone loss in a variety of pathologic conditions for over 30 years. More potent amino bisphosphonates have increased efficacy than earlier drugs, but side effects such as upper gastrointestinal symptoms and the requirement to take them at least 2 h before food have limited patient compliance. This, coupled with the growing knowledge of the pathways regulating osteoclast function, has driven efforts to identify small molecular lead compounds that could be developed into new therapeutic agents with efficacy that matches or supersedes that of bisphosphonates for the prevention of bone loss. In this article, we review briefly the effects of specific inhibitors of bone resorption that have been developed to date and highlight in a variety of models of increased bone resorption the effects of Src kinase inhibitors that have been targeted to bone to limit potential unwanted side effects on other cells.
Boyce
Brendan F
BF
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY, 14642, USA. brendan_boyce@urmc.rochester.edu
Xing
Lianping
L
Yao
Zhenqiang
Z
Shakespeare
William C
WC
Wang
Yihan
Y
Metcalf
Chester A
CA
Sundaramoorthi
Raji
R
Dalgarno
David C
DC
Iuliucci
John D
JD
Sawyer
Tomi K
TK
D001847:Bone Diseases / Q000188:drug therapy*; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D010010:Osteoclasts / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000037:antagonists & inhibitors; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; D020123:Sirolimus