Dataset Information

Both JNK1 and JNK2 Are Indispensable for Sensitized Extracellular Matrix Mineralization in IKK?-Deficient Osteoblasts.

ABSTRACT: Extracellular matrix mineralization is critical for osteogenesis, and its dysregulation could result in osteoporosis and vascular calcification. IKK/NF-?B activation inhibits differentiation of osteoblasts, and reduces extracellular matrix mineralization, however the underlying mechanisms are poorly understood. In this study, we used CRISPR/Cas9 system to permanently inactivate IKK? in preosteoblast cells and confirmed that such cells displayed dramatic increase in extracellular matrix mineralization associated with JNK phosphorylation. Such observation was also found in our study using IKK?-deficient primary murine osteoblasts. Interestingly, we found that in Ikbkb -/- Mapk8 -/- or Ikbkb -/- Mapk9 -/- double knockout cells, the enhanced mineralization caused by IKK? deficiency was completely abolished, and deletion of either Mapk8 or Mapk9 was sufficient to dampen c-Jun phosphorylation. In further experiments, we discovered that absence of JNK1 or JNK2 on IKK?-deficient background resulted in highly conserved transcriptomic alteration in response to osteogenic induction. Therefore, identification of the indispensable roles of JNK1 and JNK2 in activating c-Jun and promoting osteoblast differentiation on IKK?-deficient background provided novel insights into restoring homeostasis in extracellular matrix mineralization.

SUBMITTER: Hao Q

PROVIDER: S-EPMC7028708 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Both JNK1 and JNK2 Are Indispensable for Sensitized Extracellular Matrix Mineralization in IKKβ-Deficient Osteoblasts.

Hao Qianyun Q Liu Zhuangzhuang Z Lu Liaoxun L Zhang Lichen L Zuo Li L

Frontiers in endocrinology 20200212

Extracellular matrix mineralization is critical for osteogenesis, and its dysregulation could result in osteoporosis and vascular calcification. IKK/NF-κB activation inhibits differentiation of osteoblasts, and reduces extracellular matrix mineralization, however the underlying mechanisms are poorly understood. In this study, we used CRISPR/Cas9 system to permanently inactivate IKKβ in preosteoblast cells and confirmed that such cells displayed dramatic increase in extracellular matrix mineraliz ...[more]

PMID: 32117051

Similar Datasets

Project description:c-Jun N-terminal kinase (JNK) 1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated via phosphorylation in response to acetaminophen- or carbon tetrachloride (CCl4)-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissue from patients and in mice with genetic deletion of JNK in hepatocytes.We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, nonsteroidal anti-inflammatory drugs, or autoimmune hepatitis) or patients without acute liver failure (controls) collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and Western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1(?hepa)) or combination of Jnk1 and Jnk2 (Jnk(?hepa)), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes.Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to Jnk(?hepa) mice produced a greater level of liver injury than that observed in Jnk1(?hepa) or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in Jnk(?hepa) mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared with Jnk1(?hepa) or control mice. Hepatocytes from Jnk(?hepa) mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of adenosine monophosphate-activated protein kinase, total protein adenosine monophosphate-activated protein kinase levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected Jnk(?hepa) and control mice from liver injury.In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects.

Dataset Information

Both JNK1 and JNK2 Are Indispensable for Sensitized Extracellular Matrix Mineralization in IKK?-Deficient Osteoblasts.

Publications

Both JNK1 and JNK2 Are Indispensable for Sensitized Extracellular Matrix Mineralization in IKKβ-Deficient Osteoblasts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets