Mechanisms of interferon-beta effects on bone homeostasis.
Restoration of dysregulated bone homeostasis is a therapeutic goal in many diseases including osteoporosis, rheumatoid arthritis and metastatic cancer. The molecular pathways regulating bone remodeling are major therapeutic targets, and studies continue to reveal endogenous factors that may be pathologically up- or down-regulated and lead to an uncoupling of bone formation and resorption. The purpose of this commentary is to highlight new mechanisms of bone homeostatic regulation mediated through the induction of endogenous interferon-beta (IFN-beta). The receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) is an important factor in the bone resorption cascade, and the RANK-RANKL interaction has been shown to induce IFN-beta and osteoclastogenesis via induction of the c-fos gene. Subsequent binding of IFN-beta to its biological receptor initiates a signal transduction cascade through the classic JAK/STAT pathway, causing an inhibition of c-fos protein production and osteoclast proliferation and differentiation (negative feedback). Another mechanism pertinent to the anti-resorptive effect of IFN-beta is the induction of nitric oxide which has been shown to inhibit osteoclast formation. The role of IFN-beta in bone metabolism could warrant its systematic evaluation as a potential adjunct to therapeutic regimens of osteolytic diseases. Here we also provide discussion of the potential challenges to optimizing IFN-beta pharmacotherapy for such purposes.
Abraham
Anson K
AK
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260, USA.
Ramanathan
Murali
M
Weinstock-Guttman
Bianca
B
Mager
Donald E
DE
D001847:Bone Diseases / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D053245:RANK Ligand / Q000502:physiology; D015398:Signal Transduction
D053245:RANK Ligand; D016899:Interferon-beta