Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro

Garrett, I. Ross; Chen, D.; Gutiérrez, Gloria; Zhao, Ming; Escobedo, A.; Rossini, Gianni; Harris, S. E.; Gallwitz, Wolfgang E.; Kim, K.B.; Hu, Sheng-Zhi; Crews, Craig M.; Mundy, Gregory R.

doi:10.1172/jci16198

Cited by 297 publications

(290 citation statements)

References 34 publications

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“…Note, that the incubation of proteasomes with MG132 inhibitor almost completely abolished the chymotrypsin-specific activity, which, according to several studies, plays the most important role in terminal differentiation of various cell types, including the erythroid one. 59,60 We observed a modest decrease (20%) in the level of c-myc mRNA after addition of proteasomes to non-differentiated cells (Fig. 6B, left).…”

Section: And 3)mentioning

confidence: 85%

26S proteasome exhibits endoribonuclease activity controlled by extra-cellular stimuli

Куличкова¹,

Цимоха²,

Fedorova³

et al. 2010

Cell Cycle

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Section: And 3)mentioning

confidence: 85%

26S proteasome exhibits endoribonuclease activity controlled by extra-cellular stimuli

Куличкова¹,

Цимоха²,

Fedorova³

et al. 2010

Cell Cycle

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“…Indeed, we observed that Gli2 expression appeared to be moderately higher than Gli3 expression in C3H10T1/2 cells. Gli3 is ubiquitinated by SCF ubiquitin ligase complex, and subsequently Gli3 is degraded or cleaved into a suppressive form that works as a dominant-negative Gli3 (Garrett et al, 2003). Although the involvement of Ihh signaling in Gli3 ubiquitination is unknown at present, it might be possible that Ihh dynamically alters the expression and protein processing of Gli3.…”

Section: Discussionmentioning

confidence: 99%

“…Because hedgehog has been shown to function as an upstream of BMP in several systems (Garrett et al, 2003;Zhao et al, 2006), we examined the effect of BMP antagonist, Noggin, in C3H10T1/2 cells. Noggin effectively abolished BMP2-induced ALP activity, but only partially suppressed Ihh-induced ALP activity in C3H10T/2 cells ( Figure 5A).…”

Section: Ihh/gli2 Signaling Stimulates Bmp2-induced Osteoblast Differmentioning

confidence: 99%

Ihh/Gli2 Signaling Promotes Osteoblast Differentiation by Regulating Runx2 Expression and Function

Shimoyama

Wada

Ikeda

et al. 2007

MBoC

156

115

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Genetic and cell biological studies have indicated that Indian hedgehog (Ihh) plays an important role in bone development and osteoblast differentiation. However, the molecular mechanism by which Ihh regulates osteoblast differentiation is complex and remains to be fully elucidated. In this study, we investigated the role of Ihh signaling in osteoblast differentiation using mesenchymal cells and primary osteoblasts. We observed that Ihh stimulated alkaline phosphatase (ALP) activity, osteocalcin expression, and calcification. Overexpression of Gli2-but not Gli3-induced ALP, osteocalcin expression, and calcification of these cells. In contrast, dominant-negative Gli2 markedly inhibited Ihh-dependent osteoblast differentiation. Ihh treatment or Gli2 overexpression also up-regulated the expression of Runx2, an essential transcription factor for osteoblastogenesis, and enhanced the transcriptional activity and osteogenic action of Runx2. Coimmunoprecipitation analysis demonstrated a physical interaction between Gli2 and Runx2. Moreover, Ihh or Gli2 overexpression failed to increase ALP activity in Runx2-deficient mesenchymal cells. Collectively, these results suggest that Ihh regulates osteoblast differentiation of mesenchymal cells through up-regulation of the expression and function of Runx2 by Gli2.

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“…Bortezomib (Velcade™; PS-341) is a potent inhibitor of myeloma cell growth and survival in vitro and results indicate striking therapeutic efficacy and acceptable toxicity profile of intravenous bortezomib in myeloma patients when administered alone or in combination with dexamethasone and/or chemotherapeutic agents, after relapse or at first presentation (70)(71)(72)(73)(74). In addition to myeloma cells, osteoblasts are also sensitive to proteasome inhibitors, and we have recently shown that structurally-unrelated inhibitors of the ubiquitin-proteasome pathway (including bortezomib) have beneficial anabolic effects on the skeleton in vivo (60,75).…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

152

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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Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro

Cited by 297 publications

References 34 publications

26S proteasome exhibits endoribonuclease activity controlled by extra-cellular stimuli

26S proteasome exhibits endoribonuclease activity controlled by extra-cellular stimuli

Ihh/Gli2 Signaling Promotes Osteoblast Differentiation by Regulating Runx2 Expression and Function

The pathogenesis of the bone disease of multiple myeloma

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