Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function

Zavrski, Ivana; Krebbel, Holger; Wildemann, Britt; Heider, Ulrike; Kaiser, Martin; Possinger, K.; Sezer, Orhan

doi:10.1016/j.bbrc.2005.05.098

Cited by 90 publications

(77 citation statements)

References 29 publications

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“…Furthermore, proteasome inhibitors have also recently been demonstrated to inhibit osteoclast formation and bone resorption (76). These studies suggest that the effects of bortezomib in myeloma may be due, at least in part, to the direct effects of proteasome inhibitors to prevent myeloma bone disease.…”

Section: Proteasome Inhibitorsmentioning

confidence: 94%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

150

120

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Multiple myeloma is a fatal hematologic malignancy associated with clonal expansion of malignant plasma cells within the bone marrow and the development of a destructive osteolytic bone disease. The principal cellular mechanisms involved in the development of myeloma bone disease are an increase in osteoclastic bone resorption, and a reduction in bone formation. Myeloma cells are found in close association with sites of active bone resorption, and the interactions between myeloma cells, and other cells within the specialized bone marrow microenvironment are essential, both for tumor growth and the development of myeloma bone disease. This review discusses the many different factors which have been implicated in myeloma bone disease, including the evidence for their role in myeloma and subsequent therapeutic implications.

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Section: Proteasome Inhibitorsmentioning

confidence: 94%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

150

120

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show abstract

“…16,37,38 In addition, a recent study using the specific proteasome inhibitors MG132 and MG262 revealed that inhibition of proteasomal-ubiquitin degradation pathway suppresses RANKL-induced osteoclastogenesis. 39 Although the precise mechanism underlying this phenomenon, as well as p62 involvement in proteasome-ubiquitin system in RANKL-mediated osteoclast differentiation and function, requires further investigation, it is tempting to speculate that its interaction with TRAF6 contributes to this process. TRAF6 has been shown to be a key signaling adaptor molecule during RANKL-mediated osteoclastogenesis.…”

mentioning

confidence: 99%

p62 Ubiquitin Binding-Associated Domain Mediated the Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclast Formation

Yip

Feng

Pavlos

et al. 2006

The American Journal of Pathology

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Paget's disease of bone (PDB) is a debilitating bone disorder characterized by giant osteoclasts, enhanced bone destruction, and irregular bone formation. Recently, mutations in SQSTM1 (also known as p62) have been detected in PDB sufferers, with all mutations resulting in either loss of function or truncation/deletion of the ubiquitin binding-associated (UBA) domain. We hypothesized that mutation in the p62 gene resulting in either deletion or premature termination of the UBA domain accounts for the elevated osteoclastic formation and bone resorption associated with PDB. Remarkably, overexpression of the p62 UBA domain deletion mutant (p62⌬UBA) significantly enhanced osteoclastogenesis in vitro compared to cells expressing either wild-type p62 (p62WT) or a control vector in a RAW264.7 osteoclastogenic system. Overexpression of p62⌬UBA potentiated the formation of abnormally large multinucleated osteoclasts and resorption of bone, reminiscent of PDB. Consistent with the enhancement of osteoclastogenesis, overexpression of p62⌬UBA potentiated receptor activator of nuclear factor-B ligandinduced activation of nuclear factor-B, NFAT, and ERK phosphorylation. Paget's disease of bone (PDB) is a chronic focal skeletal disorder that is characterized by excessive osteoclast formation and activity followed by irregular new bone formation. The pathogenesis of PDB is thought to be initiated by the formation of giant osteoclasts followed by the deposition of primitive coarse-fibered bone in discontinuous trabeculae with a disjointed lamellar pattern. Although the precise etiology of PDB is presently unknown, several factors, including paramyxoviral infection and putative genetic factors are thought to contribute to its progression.

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“…97,98 Recently, another HDAC inhibitor, PXD 101, was also shown to inhibit osteoclast formation synergistically with bortezomib. 99 Finally, other proteasome inhibitors, such as MG-132 and MG-262, reduce both osteoclast differentiation and activity of mature osteoclasts in vitro; 78,100 and others, such as epoxomicin, PS-1 and lactacystin, induce osteoblast function and bone formation. 81 An interesting agent that seems to also restore osteoblast function is SB431542, an inhibitor of TGF-b type I receptor kinase.…”

Section: Effect Of Other Novel Anti-myeloma Agents On Bone Metabolismmentioning

confidence: 99%

The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma

2007

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Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein.Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.

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Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function

Cited by 90 publications

References 29 publications

The pathogenesis of the bone disease of multiple myeloma

The pathogenesis of the bone disease of multiple myeloma

p62 Ubiquitin Binding-Associated Domain Mediated the Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclast Formation

The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma

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