RANKL Up-regulates Brain-type Creatine Kinase via Poly(ADP-ribose) Polymerase-1 during Osteoclastogenesis

Chen, Jianfeng; Sun, Yan; Mao, Xia; Liu, Qizhan; Wu, Hui; Chen, Yabing

doi:10.1074/jbc.m110.157743

Cited by 27 publications

(27 citation statements)

References 54 publications

(64 reference statements)

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“…This is known as “knockdown” [42]. As an example of this, others have demonstrated that when lentiviral constructs expressing a specific shRNA sequence were introduced to BMMs, expression of the protein PARP-1 could be reduced substantially [48]. In light of these previous findings, it was thought that a similar approach could be used to elucidate, at least in part, the biological functions of CD109 in OCG by introducing shRNA sequences for this mRNA in order to develop stable CD109 knockdown cell lines.…”

Section: Discussionmentioning

confidence: 99%

CD109 Plays a Role in Osteoclastogenesis

et al. 2013

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Osteoclasts are large multinucleated cells that arise from the fusion of cells from the monocyte/macrophage lineage. Osteoclastogenesis is mediated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL) and involves a complex multistep process that requires numerous other elements, many of which remain undefined. The primary aim of this project was to identify novel factors which regulate osteoclastogenesis. To carry out this investigation, microarray analysis was performed comparing two pre-osteoclast cell lines generated from RAW264.7 macrophages: one that has the capacity to fuse forming large multinucleated cells and one that does not fuse. It was found that CD109 was up-regulated by>17-fold in the osteoclast forming cell line when compared to the cell line that does not fuse, at day 2 of the differentiation process. Results obtained with microarray were confirmed by RT-qPCR and Western blot analyses in the two cell lines, in the parental RAW264.7 cell line, as well as primary murine monocytes from bone marrow. A significant increase of CD109 mRNA and protein expression during osteoclastogenesis occurred in all tested cell types. In order to characterize the role of CD109 in osteoclastogenesis, CD109 stable knockdown cell lines were established and fusion of osteoclast precursors into osteoclasts was assessed. It was found that CD109 knockdown cell lines were less capable of forming large multinucleated osteoclasts. It has been shown here that CD109 is expressed in monocytes undergoing RANKL-induced osteoclastogenesis. Moreover, when CD109 expression is suppressed in vitro, osteoclast formation decreases. This suggests that CD109 might be an important regulator of osteoclastogenesis. Further research is needed in order to characterize the role played by CD109 in regulation of osteoclast differentiation.

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Section: Discussionmentioning

confidence: 99%

CD109 Plays a Role in Osteoclastogenesis

et al. 2013

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“…Interactions of the NLRP3 inflammasome with other networks such as the cytoskeleton and autophagy have also been reported (10). Finally, activation of this inflammasome has been shown to initiate caspase cascades, leading to proteolytic cleavage of poly(ADP‐ribose) polymerase 1 (PARP1) also known as ADP‐ribosyltransferase Diphtheria toxin‐like 1 (ARTD1) (11, 12), a multifunctional protein and presumptive inhibitor of osteoclast (OC) development (13, 14). Thus, inflammatory and noninflammatory pathways operate downstream of the NLRP3 inflammasome.…”

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confidence: 99%

NLRP3 mediates osteolysis through inflammation‐dependent and ‐independent mechanisms

Qu¹,

Bonar²,

Hickman-Brecks³

et al. 2014

FASEB j.

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Activating-mutations in NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) cause neonatal-onset multisystem inflammatory disease. However, the ontogeny of skeletal anomalies in this disorder is poorly understood. Mice globally expressing the D301N mutation in Nlrp3 (D303N in human) model the human phenotype, including systemic inflammation and skeletal deformities. To gain insights into the skeletal manifestations, we generated mice in which the expression of D301N Nlrp3 (Nlrp3( D301N)) is restricted to myeloid cells. These mice exhibit systemic inflammation and severe osteopenia (∼ 60% lower bone mass) similar to mice globally expressing the knock-in mutation, consistent with the paradigm of innate immune-driven cryopyrinopathies. Because systemic inflammation may indirectly affect bone homeostasis, we engineered mice in which Nlrp3( D301N) is expressed specifically in osteoclasts, the cells that resorb bone. These mice also develop ∼ 50% lower bone mass due to increased osteolysis, but there is no systemic inflammation and no change in osteoclast number. Mechanistically, aside from its role in IL-1β maturation, Nlrp3( D301N) expression enhances osteoclast bone resorbing ability through reorganization of actin cytoskeleton while promoting the degradation of poly(ADP-ribose) polymerase 1, an inhibitor of osteoclastogenesis. Thus, NLRP3 inflammasome activation is not restricted to the production of proinflammatory mediators but also leads to cytokine-autonomous responses.

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“…The proteins downregulated in the denosumab‐treated samples in both SL‐ and FO‐lesions included creatine kinase type B (KCRB), carbonic anhydrase 2 (CAH2), and serpin H1 (SERPH). KCRB is expressed in osteoclastogenesis and plays an important role in maintaining cellular homeostasis and osteoclast‐mediated bone resorption . CAH2 has been shown to mediate the production of hydrogen ions (H+) from CO 2 and H 2 O in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Protein Expression Profiles Corresponding to Histological Changes with Denosumab Treatment in Giant Cell Tumors of Bone

Suehara

Okubo

Kurihara

et al. 2019

Proteomics Clinical Apps

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Purpose Giant cell tumors of bone (GCTBs) are locally aggressive osteolytic bone tumors. Denosumab is a novel and effective therapeutic option for aggressive and recurrent GCTBs. Histologically, the post‐denosumab‐treated samples are characterized by two lesions: a residual stromal cell lesion with a few multinucleated giant cells (SL‐lesion), and a fibro‐osseous lesion (FO‐lesion). Experimental design To clarify the differences in the protein expression between the SL‐lesion and FO‐lesion in GCTB treated with denosumab, comparative proteomic studies are conducted using both lesions (12 pairs of pre‐ and post‐denosumab treatment samples) by isobaric tags for relative and absolute quantification (i‐TRAQ). Results Thirty‐two consistently regulated proteins in the SL‐lesions and 59 consistently regulated proteins in the FO‐lesions are found. Twenty‐one proteins in the SL‐lesion and 48 proteins in the FO‐lesion are independently expressed. These proteins may be involved in the process of the fibro‐osseous reactions by denosumab treatment. In the software program used to establish these profiles, several canonical pathways are identified, including the unfolded protein response as an FO‐lesion specific pathway. Conclusions and clinical relevance It is believed that the identified proteins and the results of the network analysis will provide a better understanding of the effects of denosumab in GCTB.

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RANKL Up-regulates Brain-type Creatine Kinase via Poly(ADP-ribose) Polymerase-1 during Osteoclastogenesis

Cited by 27 publications

References 54 publications

CD109 Plays a Role in Osteoclastogenesis

CD109 Plays a Role in Osteoclastogenesis

NLRP3 mediates osteolysis through inflammation‐dependent and ‐independent mechanisms

Protein Expression Profiles Corresponding to Histological Changes with Denosumab Treatment in Giant Cell Tumors of Bone

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