Stage-Specific Secretion of HMGB1 in Cartilage Regulates Endochondral Ossification

Taniguchi, Noboru; Yoshida, Kenji; Itö, Tatsuo; Tsuda, Masanao; Mishima, Yasunori; Furumatsu, Takayuki; Ronfani, Lorenza; Abeyama, Kazuhiro; Kawahara, Kohichi; Komiya, Setsuro; Maruyama, Ikuro; Lotz, Martin; Bianchi, Marco E.; Asahara, Hiroshi

doi:10.1128/mcb.00130-07

Cited by 86 publications

(109 citation statements)

References 59 publications

(67 reference statements)

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“…HMGB1 KO mice die shortly after birth but the embryos reveal that long bone development is significantly compromised, whereas the calvaria appears unaffected HMGB1 moves from the cytosol of hypertrophic chondrocytes at the growth plate to be released into the immediate environment. The released molecule acts as a chemoattractant for invading osteoclasts, osteoblasts and endothelial cells (Taniguchi et al, 2007). This is consistent with a recent report showing differences between marrow and calvarial derived osteoblasts to recombinant HMGB1.…”

Section: Hmgb1 and Bonesupporting

confidence: 92%

Orthodontic mechanotransduction and the role of the P2X7 receptor

Viecilli

Katona

Chen

et al. 2009

American Journal of Orthodontics and Dentofacial Orthopedics

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DEDICATIONTo my parents, who have supported my education. iv ACKNOWLEDGMENTSOne of the most important things I have learned during my PhD is the necessity of the existence of a working network of people that can help you achieve your goals. The more effectively this network functions, the higher the chance you will achieve the goals quickly.I would first like to thank my parents, who have unconditionally supported my decision to abandon a profitable private practice in Orthodontics, and return to humble student conditions while aiming for a full time academic career.I also thank my girlfriend Laura Kruter who has (almost always) been ok with my, some might say, not very sane ideas. Sometimes they do turn out fine, though (like this "PhD" one).I can hardly think of anyone else that could have complemented my work and ideas during this Program as well as Dr. Thomas Katona. While I was passionately conditioned to an idea, he was always rational and careful. While I was sometimes furious with a shortcoming, he was always temperate and humorous. When I ran into his office with some news about a project, he would always listen and almost never seem too busy to see me. While I was working and something went wrong, he would listen and wonder with me about the "whys" and "hows", instead of telling me what to do or express disappointment. He was even subject to some of my home culinary experiments. I was extremely fortunate to find someone that thought about science the same way I did, and that actually helped me with my project instead of just telling me what to do. I felt like we worked as a team, and that helped to increase my motivation during my studies. The third part of this project tested the role of the P2X7 receptor in the dentoalveolar morphology of C57B/6 mice. P2X7R KO (knockout) mice were compared to C57B/6 WT to identify differences in a maxillary molar and bone. Tooth dimensions viii were measured and 3D bone morphometry was conducted. No statistically significant differences were found between the two mouse types. P2X7R does not have a major effect on alveolar bone or tooth morphology.The final part examines the role of the P2X7 receptor in a controlled biomechanical model. Orthodontic mechanotransduction was compared in wild-type (WT) and P2X7R knock-out (KO) mice. Using Finite Element Analysis, mouse mechanics were scaled to produce typical human stress levels. Relationships between the biological responses and the calculated stresses were statistically tested and compared.There were direct relationships between certain stress magnitudes and root resorption and bone formation. Hyalinization and root and bone resorption were different in WT and KO. Orthodontic responses are related to the principal stress patterns in the PDL and the P2X7 receptor plays a significant role in their mechanotransduction.

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Section: Hmgb1 and Bonesupporting

confidence: 92%

Orthodontic mechanotransduction and the role of the P2X7 receptor

Viecilli

Katona

Chen

et al. 2009

American Journal of Orthodontics and Dentofacial Orthopedics

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“…This result is consistent with previous reports of HMGB1-induced cell migration in various cell types, such as smooth muscle cells, 21,33 fibroblasts, 45 and chondrocytes. 34 We also found that HMGB1 activated phosphorylation of ERK-1/2 in RPE cells and the migration induced by HMGB1 was dependent on ERK phosphorylation. The phosphorylation of ERK is associated with cell proliferation and cell migration through effects on cell-matrix contacts.…”

Section: Hmgb1 In Retinal Detachment N Arimura Et Alsupporting

confidence: 51%

“…21,33,34 We investigated whether HMGB1 is also a chemoattractant for RPE cells. Extracellular HMGB1 has been reported to engage multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors 2 and 4.…”

Section: Rpe Cells Respond Chemotactically To Extracellular Hmgb1 Thrmentioning

confidence: 99%

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment

Arimura

Kii

Hashiguchi

et al. 2009

Laboratory Investigation

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High-mobility group box 1 (HMGB1) protein is a multifunctional protein, which is mainly present in the nucleus and is released extracellularly by dying cells and/or activated immune cells. Although extracellular HMGB1 is thought to be a typical danger signal of tissue damage and is implicated in diverse diseases, its relevance to ocular diseases is mostly unknown. To determine whether HMGB1 contributes to the pathogenesis of retinal detachment (RD), which involves photoreceptor degeneration, we investigated the expression and release of HMGB1 both in a retinal cell death induced by excessive oxidative stress in vitro and in a rat model of RD-induced photoreceptor degeneration in vivo. In addition, we assessed the vitreous concentrations of HMGB1 and monocyte chemoattractant protein 1 (MCP-1) in human eyes with RD. We also explored the chemotactic activity of recombinant HMGB1 in a human retinal pigment epithelial (RPE) cell line. The results show that the nuclear HMGB1 in the retinal cell is augmented by death stress and upregulation appears to be required for cell survival, whereas extracellular release of HMGB1 is evident not only in retinal cell death in vitro but also in the rat model of RD in vivo. Furthermore, the vitreous level of HMGB1 is significantly increased and is correlated with that of MCP-1 in human eyes with RD. Recombinant HMGB1 induced RPE cell migration through an extracellular signalregulated kinase-dependent mechanism in vitro. Our findings suggest that HMGB1 is a crucial nuclear protein and is released as a danger signal of retinal tissue damage. Extracellular HMGB1 might be an important mediator in RD, potentially acting as a chemotactic factor for RPE cell migration that would lead to an ocular pathological wound-healing response.

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“…This is consistent with previous work showing that apoptotic MLO‐Y4 osteocytic cells release HMGB1 (Charoonpatrapong et al ., 2006; Klune et al ., 2008). Further, HMGB1 is chemotactic for osteoclasts and triggers osteoclastogenesis by activating RAGE (Taniguchi et al ., 2007; Zhou et al ., 2008; Yang et al ., 2013). Consistently, inhibition of apoptosis prevents RANKL and HMGB1 release and attenuates the enhanced osteoclastogenesis and osteoclast marker expression induced by conditioned media from Cx43‐deficient osteocytes.…”

Section: Discussionmentioning

confidence: 99%

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

et al. 2017

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SummarySkeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43‐silenced MLO‐Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase‐3 activation and exhibit increased levels of apoptosis‐related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro‐survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43‐expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis‐related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high‐mobility group box‐1 (HMGB1)], and caspase‐3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1‐RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.

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Stage-Specific Secretion of HMGB1 in Cartilage Regulates Endochondral Ossification

Cited by 86 publications

References 59 publications

Orthodontic mechanotransduction and the role of the P2X7 receptor

Orthodontic mechanotransduction and the role of the P2X7 receptor

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

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