Inhibitors of heat shock protein 90 augment endothelin‑1‑induced heat shock protein 27 through the SAPK/JNK signaling pathway in osteoblasts

Fujita, Kazuo; Otsuka, Takanobu; Kawabata, Tetsu; Sakai, Go; Matsushima‐Nishiwaki, Rie; Kozawa, Osamu; Tokuda, Harukuni

doi:10.3892/mmr.2018.8878

Cited by 6 publications

(15 citation statements)

References 21 publications

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“…demonstrated that ATP at low concentrations strongly inhibited bone formation. 21 In addition, previous studies have suggested that changes in HSP, 22,23 carbohydrate metabolism 24 or glycine metabolism-related protein families 25 also disrupt the balance of bone homeostasis. Thus, these densely connected proteins may state novel ideas for thorough research and help to identify new therapeutic agents for NF1 associated with CPT.…”

Section: Discussionmentioning

confidence: 99%

Serum-derived exosomes from neurofibromatosis type 1 congenital tibial pseudarthrosis impaired bone by promoting osteoclastogenesis and inhibiting osteogenesis

Yang

Liu

et al. 2020

Exp Biol Med (Maywood)

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Treatment of congenital pseudarthrosis of the tibia (CPT) still is full of challenges in pediatric orthopedist. Serum-derived exosomes (SDEs) have been proven to be participated in bone remodeling. However, the molecular changes in SDEs of CPT children and their pathologies have not been elucidated. In this study, SDEs were isolated and purified from CPT patients (CPT-SDEs) associated with neurofibromatosis type 1 (NF1) and normal children (Norm-SDEs). Then we obtained the proteomics profile of SDEs by combining liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tandem mass tag label-based quantitation. In vitro, the efficacy of SDEs on osteoblastic differentiation of MC3T3-E1 cells and osteoclastogenesis ability of RAW264.7 cells were evaluated by quantitative real-time PCR (qRT-PCR) and cytochemical staining. In vivo, we used micro-CT to assess cortical bone mass and trabecular microstructures to reflect the influence of SDEs on bone remodeling after injection into the tail vein of rats. Based on proteomics analysis, 410 differentially expressed proteins, including 289 downregulated proteins and 121 upregulated proteins, were identified in the CPT-SDEs. These proteins have multiple biological functions associated with cellular metabolic processes, catalytic activity, and protein binding, which are important for cell differentiation and proliferation. In vitro, CPT-SDEs decreased the osteogenic differentiation of MC3T3-E1 cells and promoted the osteoclastogenesis of RAW264.7 cells. Injection of CPT-SDEs into the tail vein for two months resulted in bone loss in rats, as indicated by the decrease in trabecular and cortical bone mass. Our findings demonstrated the differences in proteins in SDEs between normal and CPT children with NF1. These differentially expressed proteins in CPT-SDEs contributed to deteriorating trabecular bone microstructures by inhibiting bone formation and stimulating bone resorption. Impact statement Congenital pseudarthrosis of the tibia (CPT) is an uncommon and puzzling disease associated with a high rate of disability. To date, the biological mechanisms related to this disease have largely not been elucidated. In this study, we determined the biological functions of serum-derived exosomes (SDEs) from children with neurofibromatosis type 1 (NF1) associated with CPT (CPT-SDEs) and compared their proteomic profiles with those of SDEs from normal children. Based on proteomics analysis, 410 differentially expressed proteins, including 289 downregulated proteins and 121 upregulated proteins, were identified in the CPT-SDEs. In addition, CPT-SDEs decreased the osteogenic differentiation of MC3T3-E1 cells and promoted the osteoclastogenesis ability of RAW264.7 cells. Moreover, injecting CPT-SDEs into the tail veins led to bone loss in rats, as detected by the reduction in trabecular and cortical bone mass. These findings indicate that CPT-SDEs impair bone quality, which may provide a reasonable explanation for the low bone quality and tibial nonunion in children with NF1 associated with congenital tibial pseudarthrosis.

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Section: Discussionmentioning

confidence: 99%

Serum-derived exosomes from neurofibromatosis type 1 congenital tibial pseudarthrosis impaired bone by promoting osteoclastogenesis and inhibiting osteogenesis

Yang

Liu

et al. 2020

Exp Biol Med (Maywood)

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“…In our previous studies, we reported that PGF 2α or thrombin stimulates the synthesis of IL‐6 via p44/42 MAPK and p38 MAPK in osteoblast‐like MC3T3‐E1 cells, and that Rho‐kinase acts at a point upstream of p38 MAPK in the signalling 22,23 . We have also demonstrated that ET‐1 stimulates the induction of HSP27 via p38 MAPK and JNK, and that BMP‐4 stimulates OPG production via p70 S6 kinase in these cells 24,25 . Additionally, we have shown that TNF‐α stimulates the synthesis of IL‐6 via p44/42 MAPK and PI3K/Akt in MC3T3‐E1 cells, and p70 S6 kinase limits the TNF‐α‐stimulated IL‐6 synthesis at a point upstream of p44/42 MAPK and Akt in MC3T3‐E1 cells 41,42 .…”

Section: Discussionmentioning

confidence: 82%

“…In addition, we demonstrated that HSP90 negatively regulates IL‐6 synthesis stimulated by prostaglandin F 2α (PGF 2α ) or thrombin in these cells 22,23 . We further reported that HSP90 could limit HSP27 expression induced by endothelin‐1 (ET‐1) 24 and positively regulate the bone morphogenetic protein‐4 (BMP‐4)‐stimulated synthesis of osteoprotegerin (OPG), an endogenous suppressor of osteoclastogenesis, in MC3T3‐E1 cells 25 . These results lead us to speculate that HSP90 might play the role of an essential modulator of osteoblast functions.…”

Section: Introductionmentioning

confidence: 93%

HSP90 inhibitors strengthen extracellular ATP‐stimulated synthesis of interleukin‐6 in osteoblasts: Amplification of p38 MAP kinase

Hioki

Tokuda

Nakashima

et al. 2020

Cell Biochemistry & Function

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Heat shock protein 90 (HSP90) is expressed ubiquitously in a variety of cell types including osteoblasts. HSP90 acts as a key driver of proteostasis under pathophysiological conditions. Here, we investigated the involvement of HSP90 in extracellular ATP‐stimulated interleukin (IL)‐6 synthesis and HSP90 downstream signalling in osteoblast‐like MC3T3‐E1 cells. In osteoblasts, extracellular ATP stimulates the synthesis of IL‐6, a bone‐remodelling agent. Geldanamycin, 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG) and onalespib, three different HSP90 inhibitors, amplified the ATP‐stimulated IL‐6 release. Geldanamycin increased IL‐6 mRNA expression elicited by ATP. ATP enhanced the triiodothyronine‐induced osteocalcin release, but HSP90 inhibitors suppressed the release. Extracellular ATP induced the phosphorylation of p44/p42 mitogen‐activated protein kinase (MAPK), p38 MAPK, c‐Jun N‐terminal kinase (JNK), p70 S6 kinase, Akt, and myosin phosphatase‐targeting subunit (MYPT), a Rho‐kinase substrate. SB203580, an inhibitor of p38 MAPK, suppressed ATP‐stimulated IL‐6 release. Inhibitors of MEK1/2 (PD98059), JNK (SP600125), upstream kinase of p70 S6 kinase (rapamycin) and Akt (deguelin), all increased IL‐6 release. Y27632, a Rho‐kinase inhibitor, failed to affect the IL‐6 release stimulated by ATP. Geldanamycin and 17‐AAG both amplified ATP‐induced p38 MAPK phosphorylation, although geldanamycin inhibited the phosphorylation of Akt induced by ATP. In addition, SB203580 significantly reduced the amplification by geldanamycin of the IL‐6 release. Taken together, our results strongly suggest that HSP90 inhibitors up‐regulate extracellular ATP‐stimulated IL‐6 synthesis via amplification of p38 MAPK activation in osteoblasts. Significance of the study Heat shock protein 90 (HSP90) acts as a key driver of proteostasis under pathophysiological conditions in a variety of cell types. We have previously shown that HSP90 is expressed at high levels in osteoblast‐like MC3T3‐E1 cells, even in their quiescent state, consistent with HSP90 performing an important physiological function in osteoblasts. In the present study, we investigated whether HSP90 is implicated in extracellular ATP‐induced interleukin (IL)‐6 synthesis in osteoblast‐like MC3T3‐E1 cells. Our results strongly suggest that HSP90 inhibitors up‐regulate extracellular ATP‐stimulated IL‐6 synthesis via amplification of p38 mitogen‐activated protein kinase activation in osteoblasts.

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“…Hsp27 was also found to regulate lung fibroblast differentiation in response to TGF-b via activation of Smad3 and ERK-MAPK (Wang et al, 2017). Other receptor systems have also been implicated in Hsp27 signaling: These include the membrane-associated androgen receptor (Li et al, 2018) and endothelin-1 stimulation (Fujita et al, 2018). Hsp27 has further been implicated in different physiologic processes downstream of these receptors.…”

Section: Heat Shock Protein 27mentioning

confidence: 99%

The Role of Heat Shock Proteins in Regulating Receptor Signal Transduction

Streicher

2019

Mol Pharmacol

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Heat shock proteins (Hsp) are a class of stress-inducible proteins that mainly act as molecular protein chaperones. This chaperone activity is diverse, including assisting in nascent protein folding and regulating client protein location and translocation within the cell. The main proteins within the Hsp family, particularly Hsp70 and Hsp90, also have a highly diverse and numerous set of protein clients, which when combined with the high expression levels of Hsp proteins (2%-6% of total protein content) establishes these molecules as "central regulators" of cell protein physiology. Among the client proteins, Hsps regulate numerous signal-transduction and receptor-regulatory kinases, and indeed directly regulate some receptors themselves. This also makes the Hsps, particularly Hsp90, central regulators of signal-transduction machinery, with important impacts on endogenous and drug ligand responses. Among these roles, Hsp90 in particular acts to maintain mature signaling kinases in a metastable conformation permissive for signaling activation. In this review, we will focus on the roles of the Hsps, with a special focus on Hsp90, in regulating receptor signaling and subsequent physiologic responses. We will also explore potential means to manipulate Hsp function to improve receptor-targeted therapies. Overall, Hsps are important regulators of receptor signaling that are receiving increasing interest and exploration, particularly as Hsp90 inhibitors progress toward clinical approval for the treatment of cancer. Understanding the complex interplay of Hsp regulation of receptor signaling may provide important avenues to improve patient treatment.

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Inhibitors of heat shock protein 90 augment endothelin‑1‑induced heat shock protein 27 through the SAPK/JNK signaling pathway in osteoblasts

Cited by 6 publications

References 21 publications

Serum-derived exosomes from neurofibromatosis type 1 congenital tibial pseudarthrosis impaired bone by promoting osteoclastogenesis and inhibiting osteogenesis

Serum-derived exosomes from neurofibromatosis type 1 congenital tibial pseudarthrosis impaired bone by promoting osteoclastogenesis and inhibiting osteogenesis

HSP90 inhibitors strengthen extracellular ATP‐stimulated synthesis of interleukin‐6 in osteoblasts: Amplification of p38 MAP kinase

The Role of Heat Shock Proteins in Regulating Receptor Signal Transduction

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