Proteasome inhibitors and bone disease.
Bone disease in patients with multiple myeloma (MM) is characterized by increase in the numbers and activity of bone-resorpting osteoclasts and decrease in the number and function of bone-formation osteoblasts. MM-triggered inhibition of bone formation may stem from suppression of Wnt/β-catenin signaling, a pivotal pathway in the differentiation of mesenchymal stem cells (MSC) into osteoblasts, and regulating production of receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) axis by osteoblasts. Proteasome inhibitors (PIs), such as bortezomib (Bz), induce activation of Wnt/β-catenin pathway and MSC differentiation toward osteoblasts. PIs also suppress osteoclastogenesis, possibly through regulating multiple pathways including NF-κB, Bim, and the ratio of RANKL/OPG. The critical role of PI in increasing osteoblast function and suppression of osteoclast activity is highlighted by clinical evidence of increases in bone formation and decreases in bone resorption makers. This review will discuss the function of PIs in stimulating bone formation and suppression of bone resorption, and the mechanism underlying this process that leads to inhibition bone disease in MM patients.
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. yqiang@uams.edu
Ya-Wei
YW
Qiang
Christoph J
CJ
Heuck
John D
JD
Shaughnessy
Bart
B
Barlogie
Joshua
J
Epstein
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001847:Bone Diseases / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex