IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Tohmonda, Takahide; Yoda, Masaki; Iwawaki, Takao; Matsumoto, Morio; Nakamura, Masaya; Mikoshiba, Katsuhiko; Toyama, Yoshiaki; Horiuchi, Keisuke

doi:10.1172/jci76765

Cited by 55 publications

(53 citation statements)

References 55 publications

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“…Interestingly, although ROS and UPR have certain damage to normal cells, both of them are crucial factors that drive osteoclast differentiation and bone resorption 37,38 . Rac‐Nox1/2/4 and IRE1α/XBP1 are the key signaling pathways for regulating ROS and UPR, respectively; and the reason why ROS and UPR have different roles in other cell types and osteoclasts is also associated with these two pathways playing important roles in osteoclastogenesis 12,39,40 . The protective effects of ThDP in most cell types by inhibiting ROS accumulation and UPR signaling turned out to be suppressive in RANKL‐induced osteoclast differentiation and formation.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies started to recognized the significance of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress related signaling in the process of physical osteoclast differentiation. The intracellular inositol‐requiring protein‐1α/X‐box‐binding protein (IRE1α/XBP1) pathway that originally integrates UPR has been found necessary in osteoclast differentiation 12 . Furthermore, ER stress mediated eukaryotic initiation factor 2α phosphorylation and downstream activating transcription factor 4 have been demonstrated playing a direct role in regulating osteoclastogenesis 13,14 …”

Section: Introductionmentioning

confidence: 99%

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Non‐coenzyme role of vitamin B1 in RANKL‐induced osteoclastogenesis and ovariectomy induced osteoporosis

Liang

Wang

et al. 2020

J of Cellular Biochemistry

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Vitamins B are co-enzymes participating in energy metabolic pathways. While some vitamins B are known affecting bone homeostasis, the effects of vitamin B1 (thiamine) on bone health remains unclear. In our study, we used cell counting kit-8, tartrate-resistant acid phosphatase stain, actin cytoskeleton stain, and pit formation assay to evaluate the effect of thiamine on osteoclast differentiation, formation, and function, respectively. Then we used dichlorodihydro-fluorescein diacetate assay to investigate reactive oxygen species (ROS) generation and removal. Osteoporosis model by ovariectomy was established for animal experiments. We found that thiamine had inhibitory effect on osteoclast differentiation. And its inhibitory role on osteoclast differentiation is in a dosedependent way. Mechanistically, ThDP suppresses intracellular ROS accumulation and unfolded protein response signaling during osteoclastogenesis via inhibiting Rac-Nox1/2/4 and intracellular inositol-requiring protein-1α/X-boxbinding protein pathways, respectively. Osteoporotic mice treated with thiamine rich dietary showed better bone strength relative to thiamine deficient dietary. Our study explored the non-coenzyme inhibitory functions of B1 vitamin in receptor activator of nuclear factor κB ligand induced osteoclastogenesis and uncovered the significance of B1 vitamin in bone health. K E Y W O R D Snon-coenzyme, osteoclast, osteoporosis, thiamine, thiamine phosphate

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Non‐coenzyme role of vitamin B1 in RANKL‐induced osteoclastogenesis and ovariectomy induced osteoporosis

Liang

Wang

et al. 2020

J of Cellular Biochemistry

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“…Indeed, we consistently observed a UPR‐induced increase in RANKL expression in osteoblast and osteocyte cell lines, cultured neonatal calvaria, calvaria‐derived osteoblasts, and marrow‐free cortical bone preparations. It was previously reported that an increase in UPR is involved in RANKL‐stimulated osteoclastogenesis . Thus, Tm‐induced resorption observed in bone organ cultures and Tm‐induced increase in osteoclast number in mice could be due, in part, to increased UPR in these cells.…”

Section: Discussionmentioning

confidence: 88%

“…It was previously reported that an increase in UPR is involved in RANKL-stimulated osteoclastogenesis. 66 Thus, Tm-induced resorption observed in bone organ cultures and Tm-induced increase in osteoclast number in mice could be due, in part, to increased UPR in these cells. Elevated UPR has been associated with increased osteoclasts and bone loss in a rats with osteonecrosis of the femoral head, 67 mice with periodontitis induced by in P gingivalis, 68 as well as mouse models of hind limb unloading and particle-induced osteolysis.…”

Section: Discussionmentioning

confidence: 98%

Elevation of the unfolded protein response increases RANKL expression

et al. 2020

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Increased production of the osteoclastogenic cytokine RANKL is a common feature of pathologic bone loss, but the underlying cause of this increase is poorly understood. The unfolded protein response (UPR) is activated in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Failure to resolve misfolding results in excess UPR signaling that stimulates cytokine production and cell death. We therefore investigated whether RANKL is one of the cytokines stimulated in response to elevated UPR in bone cells. Pharmacologic induction of UPR with tunicamycin (Tm)‐stimulated RANKL expression in cultures of primary osteoblastic cells and in osteoblast and osteocyte cell lines. Pharmacologic inhibition of the UPR blunted Tm‐induced RANKL production. Silencing Edem1 or Sel1l, proteins that aid in degradation of misfolded proteins, also induced UPR and increased RANKL mRNA. Moreover, Tm or hypoxia increased RANKL and bone resorption in cultures of neonatal murine calvaria. Administration of Tm to adult mice caused dilation of ER in osteoblasts and osteocytes, elevated the UPR, and increased RANKL expression and osteoclast number. These findings support the hypothesis that excessive UPR signaling stimulates the expression of RANKL by osteoblasts and osteocytes, and thereby facilitates excessive bone resorption and bone loss in pathologic conditions.

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“…Primary osteoblasts were harvested from the calvaria of newborn mice as described previously. 27 For primary osteoclast culture, bone marrowederived macrophages were prepared as previously described 28 and used as osteoclast precursors. They were cultured in the presence of 50 ng/mL soluble receptor activator of NF-kB ligand and 3.3 Â 10 3 U/mL macrophageecolony stimulating factor for 5 days to induce osteoclastogenesis.…”

Section: Generation Of Hybid-deficient Micementioning

confidence: 99%

Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization Controls Endochondral Ossification through Hyaluronan Metabolism

Shimoda

Yoshida

Mizuno

et al. 2017

The American Journal of Pathology

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Hyaluronan (HA) plays an important role in the development and maintenance of tissues, and its degradation is implicated in many pathologic conditions. We recently reported that HA-binding protein involved in HA depolymerization (CEMIP; alias HYBID/KIAA1199) is a key molecule in HA depolymerization, but its developmental and pathologic functions remain elusive. We generated Hybid-deficient mice using the Cre/locus of crossover in P1 (loxP) system and analyzed their phenotypes. Hybid-deficient mice were viable and fertile, but their adult long bones were shorter than those of wild-type animals. Hybid-deficient mice showed lengthening of hypertrophic zone in the growth plate until 4 weeks after birth. There were fewer capillaries and osteoclasts at the chondroosseous junction in the Hybid-deficient mice compared with the wild-type mice. In situ hybridization demonstrated that Hybid was expressed by hypertrophic chondrocytes at the chondroosseous junction. Cultured primary chondrocytes expressed higher levels of Hybid than did osteoblasts or osteoclasts, and the Hybid expression in the chondrocytes was up-regulated after maturation to hypertrophic chondrocytes. High-molecular-weight HA was accumulated in the lengthened hypertrophic zone in Hybid-deficient mice. In addition, high-molecular-weight HA significantly reduced cell growth and tube formation in vascular endothelial growth factor-stimulated or -nonstimulated endothelial cells. HA metabolism by HYBID is involved in endochondral ossification during postnatal development by modulation of angiogenesis and osteoclast recruitment at the chondroosseous junction.

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IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Cited by 55 publications

References 55 publications

Non‐coenzyme role of vitamin B1 in RANKL‐induced osteoclastogenesis and ovariectomy induced osteoporosis

Non‐coenzyme role of vitamin B1 in RANKL‐induced osteoclastogenesis and ovariectomy induced osteoporosis

Elevation of the unfolded protein response increases RANKL expression

Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization Controls Endochondral Ossification through Hyaluronan Metabolism

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