Bortezomib inhibits human osteoclastogenesis

Abstract

In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-jB) ligand (RANKL) leads to the induction of NF-jB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-jB inhibition using bortezomib (PS-341) and I-jB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14 þ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose-and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogenactivated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-jB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.

Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma

“…20 Recent studies demonstrated that bone markers, which reflect osteoclast and osteoblast activity, can be modulated by novel agents such as proteasome inhibitors or immunmodulatory drugs. [21][22][23][24] Because of the clinical relevance of myeloma bone disease, we hypothesized that the bone resorption marker ICTP may add to the prognostic value of ISS. Thus, we evaluated the adverse prognostic impact of ICTP in combination with established prognostic factors in a patient cohort of 100 consecutive newly diagnosed patients with symptomatic MM.…”

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…In addition, Bortezomib impairs MM-BMSC interactions and modulates the OC/OB balance in the BM niche. It suppresses OC differentiation by p38 inhibition, impairment of NF-kB signaling and AP1 [79]. Importantly, it has a strong anabolic activity, which relies on proteasome inhibition and partly on DKK1 downregulation [80].…”

The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group

“…Moreover, bone turnover markers have been used to follow myeloma bone disease during specific therapies. [8][9][10] However, at present there is no consensus for the use of bone turnover markers in MM. This report of the International Myeloma Working Group summarizes the existing data for the role of markers of bone remodeling in assessing the extent of myeloma bone disease and in monitoring bone turnover during anti-myeloma treatment.…”